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Weekly Administration of Docetaxel and Paclitaxel in Metastatic or Advanced Breast Cancer

^a Cancer Institute, Ion Chiricuta Cluj-Napoca, Romania; ^b Mayo Clinic and Mayo Foundation, Jacksonville, Florida, USA

Key Words. Breast cancer • Metastatic disease • Taxanes • Chemotherapy

Correspondence: Edith A. Perez, M.D., Multidisciplinary Breast Clinic, Mayo Clinic, 4500 San Pablo Road Jacksonville, Florida 32224, USA. Telephone: 904-953-7283; Fax: 904-953-1412; e-mail: perez.edith{at}mayo.edu

Received February 11, 2005; accepted for publication August 2, 2005.

	LEARNING OBJECTIVES

Top Learning objectives Abstract Introduction Materials and methods Preliminary data with weekly... Weekly docetaxel in the... Weekly docetaxel in older... Weekly versus every-3-weeks... Weekly docetaxel-based... Randomized phase iii trials... Weekly paclitaxel in mbc Weekly paclitaxel in older... Weekly versus every-3-weeks... Weekly paclitaxel-based... Cross-resistance among taxanes Ongoing trials of weekly... Conclusions Disclosure of potential... References

 
After completing this course, the reader will be able to:

1. Identify the response rates to weekly paclitaxel and docetaxel for metastatic breast cancer.
   
2. Name the recommended doses of each taxane when administered weekly.
   
3. Learn schemas of phase III adjuvant trials incorporating weekly taxanes.
   

	ABSTRACT

Top Learning objectives Abstract Introduction Materials and methods Preliminary data with weekly... Weekly docetaxel in the... Weekly docetaxel in older... Weekly versus every-3-weeks... Weekly docetaxel-based... Randomized phase iii trials... Weekly paclitaxel in mbc Weekly paclitaxel in older... Weekly versus every-3-weeks... Weekly paclitaxel-based... Cross-resistance among taxanes Ongoing trials of weekly... Conclusions Disclosure of potential... References

 
The taxanes docetaxel (Taxotere^®; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com) and paclitaxel (Taxol^®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) have significant clinical activity in metastatic breast cancer. A number of clinical trials have evaluated the tolerability and efficacy of weekly taxane administration to optimize the benefit-to-risk ratio in metastatic breast cancer. Single-agent studies with docetaxel and paclitaxel in metastatic breast cancer show clinically significant antitumor activity even in advanced, heavily pretreated, resistant, and/or refractory disease. This activity is also evident with taxane-based combination regimens. Severe hematologic and nonhematologic toxicities are infrequent, with other toxicities noted based on the dose and weekly regimen selected. Weekly docetaxel and paclitaxel regimens represent valuable therapeutic options for women with metastatic breast cancer and have entered evaluation as part of adjuvant therapy for this disease.

	INTRODUCTION

Top Learning objectives Abstract Introduction Materials and methods Preliminary data with weekly... Weekly docetaxel in the... Weekly docetaxel in older... Weekly versus every-3-weeks... Weekly docetaxel-based... Randomized phase iii trials... Weekly paclitaxel in mbc Weekly paclitaxel in older... Weekly versus every-3-weeks... Weekly paclitaxel-based... Cross-resistance among taxanes Ongoing trials of weekly... Conclusions Disclosure of potential... References

 
An estimated 215,990 women will be diagnosed with breast cancer in the U.S. in 2005, and 40,110 deaths are expected to result from the disease [1]. For most women diagnosed with metastatic breast cancer (MBC), median survival durations of 18–36 months after diagnosis are common, with survival longer than 5–10 years reported in some cases [2]. Because palliation is an important component of treatment of systemic disease, the goals of therapy are focused on prolonging life, providing cancer-related symptom relief, minimizing treatment-related toxicity, and improving quality of life [2].

The taxanes docetaxel (Taxotere^®; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com) and paclitaxel (Taxol^®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) are now a mainstay in the treatment of MBC. The taxanes exert their antitumor activity by binding tubulin and stabilizing nonfunctional microtubule bundles, thereby blocking normal mitotic spindle development and subsequent cell division [3]. Although synthesis of paclitaxel and its analogue, docetaxel, first began in the late 1970s and early 1980s [3, 4], clinical development of the taxanes for breast cancer treatment burgeoned in the 1990s, when the antitumor activity of single-agent regimens in patients with advanced disease began to be documented in phase II trials [5, 6].

Since then, these agents have rapidly become incorporated into breast cancer treatment regimens based on data from prospective randomized phase III studies. Overall survival with single-agent paclitaxel or docetaxel is comparable with that with the previous gold-standard anthracycline, doxorubicin (Adriamycin^®; Bedford Laboratories, Bedford, OH, http://www.bedfordlabs.com) [7–9], but these agents are associated with a more favorable toxicity profile [8, 9]. In fact, both paclitaxel and docetaxel have particularly noteworthy clinical activity in anthracycline-resistant disease [10–14].

Currently, the U.S. Food and Drug Administration–approved dosing schedules for the taxanes in MBC are 60–100 mg/m² for docetaxel as a 1-hour i.v. infusion every 3 weeks and 175 mg/m² for paclitaxel as a 3-hour i.v. infusion every 3 weeks. One of the most frequent dose-limiting adverse effects with every-3-weeks taxane therapy is myelo-suppression, primarily neutropenia [4, 5]. The most frequent nonhematologic toxicities include neuropathy, myalgias, fatigue, gastrointestinal disturbances, mucosal toxicity, and skin and nail changes [4, 5, 15]. To reduce docetaxel-induced fluid retention and hypersensitivity, corticosteroid premedication is frequently administered [4, 5, 15]. All patients receiving paclitaxel should be pretreated with corticosteroids, diphenhydramine, and H₂-receptor antagonists to prevent hypersensitivity reactions [16].

Studies have evaluated weekly administration of the taxanes as a strategy to maintain or improve upon the efficacies of conventional schedules and to achieve a more favorable toxicity profile [17]. By administering lower doses more frequently, toxicity may be decreased while maintaining the dose intensity necessary for anti-tumor activity. This review summarizes the extensive clinical data that have been published on the administration of weekly docetaxel and paclitaxel, as single-agent therapy and as part of combination regimens, for the treatment of MBC.

	MATERIALS AND METHODS

Top Learning objectives Abstract Introduction Materials and methods Preliminary data with weekly... Weekly docetaxel in the... Weekly docetaxel in older... Weekly versus every-3-weeks... Weekly docetaxel-based... Randomized phase iii trials... Weekly paclitaxel in mbc Weekly paclitaxel in older... Weekly versus every-3-weeks... Weekly paclitaxel-based... Cross-resistance among taxanes Ongoing trials of weekly... Conclusions Disclosure of potential... References

 
In an attempt to comprehensively analyze the published evidence regarding the use of weekly taxanes in MBC or advanced breast cancer, we conducted electronic searches using the Ovid MEDLINE database for records using the subject headings "breast neoplasms" and "taxoids" and the key word "weekly." Additionally, the abstract books from key international meetings, that is, the American Society of Clinical Oncology (ASCO) Annual Meeting, the European Society for Medical Oncology (ESMO) Congress, the San Antonio Breast Cancer Symposium (SABCS), and the St Gallen Primary Therapy of Early Breast Cancer meeting (St Gallen, Switzerland), were manually searched for relevant study reports. We also backtracked relevant references from the identified articles to further refine the search. Because of the large number of abstracts and articles identified, only those studies that we considered most relevant are presented and discussed here.

	PRELIMINARY DATA WITH WEEKLY TAXANES IN SOLID TUMORS

Top Learning objectives Abstract Introduction Materials and methods Preliminary data with weekly... Weekly docetaxel in the... Weekly docetaxel in older... Weekly versus every-3-weeks... Weekly docetaxel-based... Randomized phase iii trials... Weekly paclitaxel in mbc Weekly paclitaxel in older... Weekly versus every-3-weeks... Weekly paclitaxel-based... Cross-resistance among taxanes Ongoing trials of weekly... Conclusions Disclosure of potential... References

 
Weekly taxane dosing was studied in numerous phase I and II trials of patients with MBC and other advanced solid tumors. Several dosing regimens were evaluated, including: (a) dosing for 2- or 3-week periods followed by a 1-week no-treatment "rest" period [18–20], (b) dosing for 4–6 weeks followed by a 2-week rest period [21, 22], and (c) continuous weekly dosing without a rest period [23–25]. For docetaxel, the infusion duration varied among studies, with the majority using a 1-hour i.v. infusion, which is recommended in current labeling, while two studies used a shorter infusion time (15–30 minutes) [22, 23]. For paclitaxel, the infusion duration was 1 hour in all studies.

The maximum-tolerated dose of docetaxel ranged around 40 mg/m², depending on the dosing frequency. Dose-limiting toxicities (DLTs) included myelosuppression (most commonly neutropenia with and without fever), fatigue, asthenia, and gastrointestinal symptoms including diarrhea; nail changes were also noted. The most frequently recommended dose for future studies was 35–40 mg/m² per week, but lower doses are now being used to improve tolerability. On the other hand, the maximum-tolerated dose of paclitaxel in initial studies was 100–110 mg/m² weekly. The DLT was primarily neutropenia, with and without fever, resulting in recommended doses for future studies of 80–100 mg/m² per week. The antitumor activity observed in these studies was promising, given that all study populations were patients with advanced malignancies, many of whom were refractory to prior chemotherapy regimens.

	WEEKLY DOCETAXEL IN THE TREATMENT OF MBC

Top Learning objectives Abstract Introduction Materials and methods Preliminary data with weekly... Weekly docetaxel in the... Weekly docetaxel in older... Weekly versus every-3-weeks... Weekly docetaxel-based... Randomized phase iii trials... Weekly paclitaxel in mbc Weekly paclitaxel in older... Weekly versus every-3-weeks... Weekly paclitaxel-based... Cross-resistance among taxanes Ongoing trials of weekly... Conclusions Disclosure of potential... References

 
Weekly Single-Agent Docetaxel
Weekly administration of docetaxel has been evaluated in several phase II trials of women with MBC (Table 1) [26–38]. Most patients in those studies had received prior chemotherapy for MBC and most had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1. Stemmler et al. [34] reported median times to progression (TTPs) of 6.6 months in chemotherapy-naïve patients and 5.9 months in pretreated patients; likewise, Aihara et al. [35] and Kim et al. [27] reported a median TTP of 5 months. In patients resistant to anthracyclines, Ramos et al. [29] reported 8.4 months as the median time to disease progression. The median overall survival in these trials ranged from 13–14 months [29, 34–36]. The weekly docetaxel regimens were well tolerated, and grade 4 toxicities were rare. The most common grade 3 toxicities included neutropenia, anemia, and fatigue/asthenia; ocular toxicity manifesting as increased lacrimation resulting from canalicular stenosis [37] and nail toxicities were also notable. Stemmler et al. randomized patients to receive either dexamethasone (Decadron^®; Merck & Co., Inc., Whitehouse Station, NJ, http://www.merck.com) premedication or no premedication; patients who received dexamethasone had a significantly lower incidence of nail changes (p = .004) and edema/effusions (p = .017) [34].

In summary, these studies show that weekly docetaxel at doses of 35–40 mg/m² has clinical activity in MBC, producing responses in 30%–40% of pretreated patients, with a median TTP of around 7 months. This schedule is associated with a low incidence of the classic grade 3–4 hematologic and nonhematologic toxicities reported with the every-3-weeks schedules.

	WEEKLY DOCETAXEL IN OLDER WOMEN

Top Learning objectives Abstract Introduction Materials and methods Preliminary data with weekly... Weekly docetaxel in the... Weekly docetaxel in older... Weekly versus every-3-weeks... Weekly docetaxel-based... Randomized phase iii trials... Weekly paclitaxel in mbc Weekly paclitaxel in older... Weekly versus every-3-weeks... Weekly paclitaxel-based... Cross-resistance among taxanes Ongoing trials of weekly... Conclusions Disclosure of potential... References

 
In view of the favorable tolerability profile of weekly docetaxel, this regimen was tested in older or frail patients. One trial [36] included 41 patients 65 years of age or those who were poor candidates for combination chemotherapy. They received docetaxel at a dose of 36 mg/m² weekly for six consecutive weeks, followed by 2 weeks without treatment. The median age of the patients in that trial was 74 years, and 73% of patients had one or more visceral sites of metastasis. Thirteen patients (36%) had objective responses to treatment, and one had a minor response. The median TTP for responding and stable patients was 7 months. The median survival duration for the entire group was 13 months, with 1- and 2-year actuarial survival rates of 61% and 29%, respectively. Grade 3–4 fatigue was the most common toxicity, occurring in 20% of patients.

Another phase II study evaluated the tolerability and activity of docetaxel (36 mg/m² per week) in 47 frail or older patients (over 70 years of age) with MBC who were considered unlikely to tolerate the every-3-weeks regimen [38]. Reasons for ineligibility to the standard every-3-weeks docetaxel (100 mg/m²) regimen were age >70 years, poor hematological reserves, impaired liver function, and intolerance to previous taxanes administered every 3 weeks without demonstrated resistance. There was a median of two prior chemotherapy regimens, and more than half of the patients had a World Health Organization (WHO) performance status score at baseline of 2–3. The incidence of serious adverse events was low. Grade 3–4 neutropenia occurred in 10 patients. Neurotoxicity was mild, and grade 3 paresthesia occurred in one patient. The overall objective response rate in 37 evaluable patients was 30%, and responses were observed in all subgroups of patients.

These results favor the use of weekly docetaxel in frail or elderly patients for which chemotherapy is indicated; it represents an active regimen with a low toxicity profile that offers the clinician a much needed treatment with a better risk-to-benefit ratio that can be safely proposed for elderly patients with extensive visceral disease.

	WEEKLY VERSUS EVERY-3-WEEKS DOCETAXEL ADMINISTRATION: RANDOMIZED PHASE II STUDY

Top Learning objectives Abstract Introduction Materials and methods Preliminary data with weekly... Weekly docetaxel in the... Weekly docetaxel in older... Weekly versus every-3-weeks... Weekly docetaxel-based... Randomized phase iii trials... Weekly paclitaxel in mbc Weekly paclitaxel in older... Weekly versus every-3-weeks... Weekly paclitaxel-based... Cross-resistance among taxanes Ongoing trials of weekly... Conclusions Disclosure of potential... References

 
A randomized phase II study was conducted at 10 centers in Spain and Belgium to compare weekly with every-3-weeks docetaxel administration in patients with MBC, and was recently reported in extended form [39]. Eighty-three patients who had received prior neoadjuvant, adjuvant, and/or first-line chemotherapy for metastatic disease (alkylating agent, anthracycline, or both) were enrolled [39]. Patients were randomized to either the weekly regimen (docetaxel, 40 mg/m² by 30-minute i.v. infusion weekly for six consecutive weeks followed by a 2-week rest) or the every-3-weeks regimen (docetaxel, 100 mg/m² by 1-hour i.v. infusion every 3 weeks). For the weekly regimen, 8 mg dexamethasone (or equivalent) was administered orally in the morning, 1-hour preinfusion, and in the evening of the dosing day. For the every-3-weeks regimen, six 8-mg doses of dexamethasone were administered orally beginning the evening prior to dosing and ending the evening of day 2 [39].

Approximately 20% of patients had received prior chemotherapy for metastatic disease. Two patients achieved complete responses and 12 achieved partial responses, for overall response rates (ORRs) of 34% (95% confidence interval [CI], 21%–51%) in the weekly group and 33% (95% CI, 20%–50%) in the every-3-weeks group. At a median follow-up of 10 months, the median TTP for patients treated with weekly docetaxel was 5.7 months, while it was 5.3 months for those treated with every-3-weeks docetaxel; the median times to treatment failure were 4.1 and 4.9 months, respectively. The incidence of all grade 3–4 adverse events was higher in the every-3-weeks group than in the weekly group (96 versus 44), and the number of patients with grade 3–4 adverse events was also greater in the every-3-weeks group (31 versus 20). The incidences of grade 3–4 adverse events in the weekly and every-3-weeks groups, respectively, were as follows: neutropenia without fever, 2% and 17%; neurotoxicity, 2% and 17%; febrile neutropenia, 5% and 20%; and stomatitis, 7% and 17%. The weekly and every-3-weeks regimens, respectively, had similar rates of other clinically relevant toxicities, such as fatigue (68% and 81%), nail toxicity (56% and 56%), tearing or watery eyes (53% and 39%), alopecia (78% and 87%), and edema (33% and 33%). Although both schedules were well tolerated, the weekly schedule had lower incidences of grade 3–4 neutropenia, neutropenic fever, stomatitis, and neurosensory toxicity [39].

Another study from Egypt randomized 30 patients to receive either weekly docetaxel (35 mg/m² for 6 weeks then 2 weeks rest) or docetaxel (100 mg/m²) every 3 weeks. The authors observed high response rates in both arms, 86.7% and 73.3%, respectively (p = .326), with less neutropenia for the weekly regimen (p = .02), while fatigue, nausea, vomiting, and fluid retention were more commonly encountered with the standard every-3-weeks schedule [40]. We can conclude that there is randomized evidence that the weekly docetaxel regimen is at least as effective as the every-3-weeks regimen and causes less neutropenia, neutropenic fever, stomatitis, and neurologic toxicity, but requires weekly outpatient visits.

	WEEKLY DOCETAXEL-BASED COMBINATION REGIMENS IN MBC

Top Learning objectives Abstract Introduction Materials and methods Preliminary data with weekly... Weekly docetaxel in the... Weekly docetaxel in older... Weekly versus every-3-weeks... Weekly docetaxel-based... Randomized phase iii trials... Weekly paclitaxel in mbc Weekly paclitaxel in older... Weekly versus every-3-weeks... Weekly paclitaxel-based... Cross-resistance among taxanes Ongoing trials of weekly... Conclusions Disclosure of potential... References

 
The promising results of studies evaluating weekly docetaxel as a single agent provide the rationale for evaluating weekly docetaxel in combination chemotherapy regimens for MBC. Phase I and phase II trials have assessed weekly docetaxel regimens in combination with anthracyclines [41–44], gemcitabine (Gemzar^®; Eli Lilly and Company, Indianapolis, http://www.lilly.com) [45–49], vinorelbine (Navelbine^®; GlaxoSmithKline, Philadelphia, http://www.gsk.com) [46, 50], and trastuzumab (Herceptin^®; Genentech, Inc., South San Francisco, CA, http://www.gene.com) [51]. The combination of two inhibitors of microtubule function, docetaxel and estra-mustine (Emcyt^®; Pfizer Pharmaceuticals, New York, http://www.pfizer.com) proved to be too toxic to be investigated further [52]. Some of the reported results are summarized in Table 2.

Docetaxel–Trastuzumab Combinations
Several phase II studies have evaluated the activity and tolerability of weekly docetaxel in combination with trastuzumab in women with MBC overexpressing human epidermal growth factor receptor-2 (HER-2). Esteva and colleagues evaluated docetaxel (35 mg/m² per week) plus trastuzumab (loading dose of 4 mg/kg, followed by 2 mg/kg thereafter) in 30 women with HER-2–overexpressing MBC (Table 2) [51]. Nineteen patients achieved partial responses, for an ORR of 63% (95% CI, 44%–80%) [51]. In the subgroup of 24 patients who were HER-2 positive by fluorescence in situ hybridization (FISH), the ORR was 67% [51]. When response was analyzed by HER-2 extra-cellular domain level, those with baseline levels >14.9 ng/ml (n = 21) had an ORR of 76%, compared with a 33% response rate in patients with levels below this threshold (p = .04) [51]. The median TTP was 9 months [51]. This suggests that the level of HER-2 extracellular domain should be investigated as a predictive factor in HER-2–overexpressing patients.

In a second phase II trial, a similar regimen was investigated, and preliminary data from 21 patients (total, 69 cycles; median follow-up, 9 months) were reported [53]. The ORR in 19 evaluable patients was 63%, and only one grade 3–4 hematologic toxicity occurred (grade 3 neutropenia). Fatigue and diarrhea were the most common grade 3 non-hematologic toxicities (each occurring in three patients), and one case of grade 4 dyspepsia/ulcer was reported [53].

A phase II multicenter randomized study conducted in Germany compared every-3-weeks docetaxel and trastuzumab with a weekly regimen as first-line therapy for patients with anthracycline-pretreated, HER-2–overex-pressing MBC (Table 2) [54]. The ORRs were 69% (95% CI, 39%–91%) in the every-3-weeks group and 54% (95% CI, 23%–83%) in the weekly group [54]. The median TTPs were 215 days and 335 days in the every-3-weeks and weekly groups, respectively. Grade 3–4 hematologic toxicities were frequent in the every-3-weeks group, including neutropenia, leukopenia, febrile neutropenia, and anemia. Only one grade 3–4 hematologic toxicity (leukopenia) occurred in the weekly group [54].

A multi-institutional phase II trial conducted in the U.S. reported an ORR of 50%, including two complete responses and 11 partial responses, with a weekly docetaxel–trastuzumab regimen as first- or second-line therapy for 26 women with previously treated, HER-2–overexpressing MBC (Table 2) [55]. Among patients that were HER-2 3+ by immunohistochemistry (IHC) (n = 19), the ORR was 63%, compared with a 14% responserate (one of seven patients) among those with HER-2 2+ tumors. The ORR among patients with HER-2–positive tumors by FISH was 64%. For the whole studied population, the median TTP was 12.4 months, and the median overall survival was 22.1 months. The regimen was well tolerated. A Brazilian multicenter phase II study evaluated weekly docetaxel and trastuzumab as primary therapy in 33 patients with locally advanced, stage III HER-2–overexpressing breast cancer for response rate, pathologic response, and safety [56]. The patients were 70% stage IIIB and 30% stage IIIA-large T3 tumors, all HER-2 3+ as determined by IHC (HercepTest^TM; DakoCytomation, Glostrup, Denmark, http://www.dako.dk). In this untreated patient population, the ORR was 70% (23/33), with a 46% partial response rate and a 24% complete response rate. The pathological complete response rate was 12% (4/33). Eight patients (24%) had negative nodes at the time of surgery. The treatment was well tolerated with only one patient (4%) experiencing grade 4 toxicity (anasarca). The most frequent grade 3 adverse events were alopecia (15%), neutropenia (9%), and headache (9%). Another phase II study was designed to determine the efficacy and toxicity of weekly docetaxel in MBC patients when given alone (for HER-2–negative disease) or with trastuzumab (for HER-2–overexpressing disease) [57]. Patients with MBC received docetaxel given on two different schedules, either 33 mg/m² or 40 mg/m², weekly for 3 weeks with 1 week off. Patients with HER-2–overexpressing disease also received trastuzumab, 4 mg/kg on day 1 then 2 mg/kg on days 8 and 15 of each 28-day cycle. Fifty-two patients were treated with docetaxel alone (35 patients) or in combination with trastuzumab (17 patients). Partial responses occurred in 7 of the 35 patients treated with docetaxel alone, including 3 of the 19 taxane-pretreated patients and 4 of the 16 taxane-naïve patients. Partial responses occurred in 10 of 17 patients (59%; 95% CI, 34%–82%) treated with docetaxel and trastuzumab. The most common grade 3–4 toxicities, occurring in at least 10% of patients, included neutropenia (21%), pulmonary toxicity (12%), and hyperglycemia (10%). The median times to disease progression were 4.5 months (95% CI, 2.5–6.5 months) in the docetaxel group and 8.5 months (95% CI, 4.5–12.5 months) in the docetaxel–trastuzumab group.

Building on preclinical data suggesting synergism between vinorelbine and docetaxel plus trastuzumab, Yardley et al. performed a phase II trial evaluating weekly trastuzumab administered with docetaxel and vinorelbine as first-line therapy of HER-2–positive MBC patients [58]. Patients received vinorelbine (25 mg/m²) and docetaxel (30 mg/m²) on days 1 and 8 every 21 days. Trastuzumab was given at a dose of 4 mg/kg on day 1 followed by 2 mg/kg per week thereafter. Grade 3–4 toxicities included neutropenia (70%), febrile neutropenia (21%), fatigue (14%), hyperglycemia (10%), and myalgias (7%). At the time of the analysis of 29 evaluable patients, the response rate was 75%, with 10 (42%) partial responses and eight (33%) complete responses. Four patients had stable disease and two had disease progression. Three deaths resulting from intercurrent illness were noted (myocardial infarction, renal failure, and gastrointestinal bleed). The progression-free survival duration was 11.3 months.

To further improve the clinical and pathologic response rates, a pilot study evaluated the safety and efficacy of preoperative epidoxorubicin (epirubicin; Ellence^®; Pfizer Pharmaceuticals) and docetaxel plus trastuzumab in 14 outpatient breast cancer patients [59]. Preoperative treatment consisted of weekly trastuzumab (4 mg/kg body weight loading dose, 2 mg/kg per week maintenance dose) in combination with weekly epidoxorubicin (30 mg/m²) and docetaxel (35 mg/m²) once a week for 6 weeks followed by 1 week off therapy. Because of possible cardiotoxic effects of the anthracycline-containing regimen in combination with trastuzumab, left ventricular ejection fraction (LVEF) was monitored twice during treatment (at the beginning and end of treatment) and every 6 months after finishing therapy. Outpatient epidoxorubicin and docetaxel plus trastuzumab were well tolerated. In two patients, WHO grade IV leukocytopenia was observed. WHO grade III toxicities consisted of leukocytopenia (10%) and stomatitis (3%). Cardiac toxicity or allergic reactions were not observed in any of the patients. Twelve (86%) of the 14 patients responded, leading to breast-conserving surgery in 11 of 14 patients (79%), with one pathological complete response.

In summary, there is compelling evidence that the docetaxel–trastuzumab combination is extremely active when used as a weekly treatment in HER-2–positive patients, with response rates in the range of 55%–75%, even in pretreated patients. The toxicity profile is very favorable, with few grade 3–4 toxicities, supporting the use of this regimen as a front-line treatment for this patient population.

	RANDOMIZED PHASE III TRIALS OF WEEKLY DOCETAXEL

Top Learning objectives Abstract Introduction Materials and methods Preliminary data with weekly... Weekly docetaxel in the... Weekly docetaxel in older... Weekly versus every-3-weeks... Weekly docetaxel-based... Randomized phase iii trials... Weekly paclitaxel in mbc Weekly paclitaxel in older... Weekly versus every-3-weeks... Weekly paclitaxel-based... Cross-resistance among taxanes Ongoing trials of weekly... Conclusions Disclosure of potential... References

 
In an attempt to supply data for the optimal management of MBC, a phase III trial was designed in Germany for MBC patients no longer eligible for anthracyclines [60]. Randomized patients received either docetaxel (35 mg/m²) or vinorelbine (30 mg/m²) weekly—6 for four cycles of 8 weeks’ duration. Crossover was offered after progression. The primary end point was TTP; other end points were survival, response, toxicity, and quality of life. Of the reported 112 patients, 57 received vinorelbine, and 55 received docetaxel. Sixty-five patients crossed over because of progressive disease and received vinorelbine (31 patients) or docetaxel (34 patients) as second therapy. The overall median follow-up was 230 days (5–1,588). Before or without crossing over, vinorelbine patients had a median of seven doses for a TTP of 81 days (95% CI, 67–99), while docetaxel patients had a median of 11 doses. Overall survival for initial vinorelbine versus docetaxel was 253 days (95% CI, 173–331) versus 288 days (95% CI, 231–424), (p = not significant [ns]). The 1-year survival rates were 31% for vinorelbine (95% CI, 20%–46%) and 44% for docetaxel (95% CI, 30%–60%). More vinorelbine patients (42%) than docetaxel patients (18%) had disease progression as their best response (p = .00751). After crossing over, docetaxel led to a higher objective response rate (35% versus 3%, p = .0014, Fisher’s exact test, double sided), but again without significant benefit in terms of TTP or overall survival. Generally, vinorelbine resulted in more treatment delays (76% versus 46%) and more leukopenia (61% versus 10%) and neutropenia (43% versus 7%), grade 3–4, but less mucositis/stomatitis (1% versus 8%, all p < .05, Fisher’s exact test, double sided).

	WEEKLY PACLITAXEL IN MBC

Top Learning objectives Abstract Introduction Materials and methods Preliminary data with weekly... Weekly docetaxel in the... Weekly docetaxel in older... Weekly versus every-3-weeks... Weekly docetaxel-based... Randomized phase iii trials... Weekly paclitaxel in mbc Weekly paclitaxel in older... Weekly versus every-3-weeks... Weekly paclitaxel-based... Cross-resistance among taxanes Ongoing trials of weekly... Conclusions Disclosure of potential... References

 
Weekly Single-Agent Paclitaxel
Like docetaxel, paclitaxel administered on a weekly schedule has been studied extensively both as a single agent and in combination chemotherapy. Common toxicities associated with every-3-weeks paclitaxel dosing include neutropenia, neuropathy, and arthralgia/myalgia. Weekly dosing of paclitaxel has been evaluated as a means to increase dose density and improve tolerability.

Several phase II studies have evaluated weekly paclitaxel administration as single-agent therapy in patients with MBC (Table 3). Seidman and colleagues evaluated continuous paclitaxel therapy, 100 mg/m² per week, in 30 women with MBC who had received prior adjuvant and/or meta-static therapy (Table 3) [61]. Three patients in that study achieved complete responses (10%) and 16 achieved partial responses (43%) for an ORR of 53% (95% CI, 34%–72%). Therapy was generally well tolerated. Grade 3–4 neutropenia occurred in four patients, with no episodes of febrile neutropenia. There was no evidence of cumulative neutropenia and no cases of thrombocytopenia. The only frequent grade 3 nonhematologic toxicity was neurosensory toxicity in seven patients (24%), five of whom had received paclitaxel doses of 110–120 mg/m² [61].

An Italian phase II study reported a single-institution experience with paclitaxel administered weekly at a dose of 90 mg/m² [63] in 58 patients with advanced breast cancer or MBC without prior taxane exposure. The authors observed a response rate of 44% in the subpopulation of patients previously treated with anthracyclines (52 patients).

A multicenter study from Japan enrolled 74 patients with advanced breast cancer or MBC, of which 66.2% had received prior anthracyclines, in a study of weekly paclitaxel (80 mg/m²) for 3 weeks followed by a 1-week rest [64]. The ORR was 40.5%, including a 4.1% complete response rate, with a median overall survival time of 15.8 months.

Other studies reported similar results [65–67]. High-dose weekly paclitaxel (175 mg/m² per week) without prophylactic growth factor support was evaluated in 34 patients with previously untreated metastatic or unresectable locally advanced breast cancer (LABC) (Table 3) [68]. The ORR was 78% (95% CI, 60%–91%), with five complete responses (16%) [68]. No significant difference in response was observed between patients with metastatic disease and those with LABC, between those with visceral disease and those with soft tissue disease, or between those who had had prior anthracycline-based adjuvant therapy and those who had not [68]. Grade 3–4 neutropenia developed in 22 patients (65%), with two patients requiring hospitalization for febrile neutropenia; grade 3 neurotoxicity was observed in four patients. This high-dose weekly regimen more than doubled the dose intensity delivered with standard every-3-weeks paclitaxel and achieved response rates comparable with those produced by combination chemotherapy.

A large, multicenter phase II study by Perez and colleagues investigated the activity and tolerability of weekly paclitaxel (80 mg/m² per week) in 212 women with previously treated MBC (Table 3) [69]. Overall, 25% of the patients had previously received taxanes using an every-3-weeks or every-4-weeks schedule, 25% had undergone two prior chemotherapy regimens for MBC, and 9% had received treatment with high-dose chemotherapy and stem cell transplant. In addition, 11% of enrolled patients presented with brain metastases. Paclitaxel was administered once weekly, without breaks, until disease progression or intolerable toxicity. In 177 evaluable patients, the ORR was 21.5% (95% CI, 15.4%–27.5%), with four complete responses [69]. The median TTP and overall survival duration were 142 days and 387 days, respectively. Grade 3–4 toxicities were limited to neutropenia, anemia, and neuropathy, and were seen in 9% of patients [69].

In summary, weekly paclitaxel produced response rates in the range of 22%–53% in pretreated patients, with a median TTP of 5–6 months. The toxicity associated with this regimen was mild and consisted mainly of neutropenia and neuropathy.

	WEEKLY PACLITAXEL IN OLDER WOMEN

Top Learning objectives Abstract Introduction Materials and methods Preliminary data with weekly... Weekly docetaxel in the... Weekly docetaxel in older... Weekly versus every-3-weeks... Weekly docetaxel-based... Randomized phase iii trials... Weekly paclitaxel in mbc Weekly paclitaxel in older... Weekly versus every-3-weeks... Weekly paclitaxel-based... Cross-resistance among taxanes Ongoing trials of weekly... Conclusions Disclosure of potential... References

 
An analysis was conducted on the subset of patients 65 years or older (<65 years [n = 139, 66%] versus =65 years [n = 73, 34%]) from the multicenter phase II study of Perez et al [69] that investigated the activity and tolerability of weekly paclitaxel (80 mg/m² per week) (Table 3) [69]. Paclitaxel was administered once weekly without breaks until disease progression or intolerable toxicity. Baseline characteristics were similar in the two age groups; however, older patients were less likely to have received prior chemotherapy, less likely to have received prior anthracycline- or taxane-based chemotherapy, and more likely to have received prior hormonal therapy (p < .005 compared with the younger patient group for all) [70]. The ORRs were not significantly different statistically between the age groups, and the tolerability profiles were similar [70]. Grade 3–4 neutropenia occurred in 15% of patients of both age groups, and grade 3 neuropathy occurred in 12% and 9% of the older and younger patients, respectively. Other toxicities of a serious nature were uncommon [70].

Similar results were recently reported from another multicenter phase II study performed in The Netherlands, which specifically evaluated the activity and toxicity of weekly paclitaxel as first-line chemotherapy in elderly patients (>70 years of age) with hormone-refractory MBC [71]. Twenty-six patients with MBC received 80 mg/m² paclitaxel administered weekly on days 1, 8, and 15 of a 28-day cycle. Additional cycles were given until disease progression or unacceptable toxicity. The protocol allowed for a dose increase to 90 mg/m² in the absence of toxicity. In 23 patients who were evaluable for response, there were 10 partial responses (38%), nine patients with stable disease (35%), and four patients with disease progression (15%). The median duration of response was 194 days (>6 months). Overall, treatment was relatively well tolerated, but eight patients (32%) had to prematurely discontinue treatment because of fatigue. Neuropathy greater than grade 1 was noted only after five or more cycles in four patients.

Along with aging of the population, breast cancer in elderly patients constitutes a major health problem that will increase in the future. As the paclitaxel weekly regimen seems to be associated with less toxicity than the every-3-weeks schedule, these weekly regimens are very attractive for elderly breast cancer patients.

	WEEKLY VERSUS EVERY-3-WEEKS PACLITAXEL ADMINISTRATION: RANDOMIZED PHASE III STUDY

Top Learning objectives Abstract Introduction Materials and methods Preliminary data with weekly... Weekly docetaxel in the... Weekly docetaxel in older... Weekly versus every-3-weeks... Weekly docetaxel-based... Randomized phase iii trials... Weekly paclitaxel in mbc Weekly paclitaxel in older... Weekly versus every-3-weeks... Weekly paclitaxel-based... Cross-resistance among taxanes Ongoing trials of weekly... Conclusions Disclosure of potential... References

 
A large phase III randomized study compared the efficacy and tolerability of two high-dose weekly paclitaxel regimens with a standard-dose weekly regimen in patients with previously treated or untreated MBC (Table 3) [72]. Patients were stratified according to prior chemotherapy and presence of liver metastases prior to randomization. The mean delivered dose intensities for the 6-week, 2-week, and 15-week regimens were 100.7 mg/m², 108 mg/m², and 76 mg/m² per week, respectively, with the 6-week and 2-week regimens delivering 25% and 46% higher dose intensities, respectively, than the 15-week regimen. The 6-week and 2-week regimens were associated with greater incidences of neutropenia (grade 4, 40% and 45%, respectively), febrile neutropenia (9% and 13%, respectively), and grade 3 sensory neuropathy (16% and 20%, respectively) than the 15-week regimen (8%, 1%, and 8%, respectively) [72]. High-dose weekly paclitaxel (6-week and 2-week regimens) did not produce a significantly higher ORR or prolong survival, and it was associated with greater toxicity, including neutropenia and neuropathy.

In an effort to determine the relative efficacy of weekly versus every-3-week spaclitaxel dosing, a randomized phase III Cancer and Leukemia Group B study compared paclitaxel (100 mg/m², modified to 80 mg/m² after the initial weeks of therapy) once weekly with paclitaxel (175 mg/m²) every 3 weeks as first-line therapy for 577 women with MBC [73]. Patients received trastuzumab if the tumor was HER-2 positive; if the tumor was HER-2 negative, patients were randomized to either receive trastuzumab or not. Weekly paclitaxel led to an ORR of 40%, compared with a response rate of 28% for the every-3-weeks regimen (odds ratio, 1.61; p = .017). The median TTPs were 9 months and 5 months for the weekly and every-3-weeks regimens, respectively (p = .0008). Weekly paclitaxel dosing resulted in more grade 3 sensory neuropathy (23% versus 12%, p = .001) and motor neuropathy (8% versus 4%, p = .04), but less grade 3 granulocytopenia (8% versus 15%, p = .013). Trastuzumab did not improve overall response in patients with HER-2–negative MBC.

These findings indicate that paclitaxel has greater efficacy in the management of MBC when administered weekly rather than every 3 weeks and that trastuzumab does not appear to improve the efficacy of paclitaxel in patients with HER-2–negative disease. Based on these data, the standard-dose weekly paclitaxel regimen is recommended over the every-3-weeks schedule as the better regimen for the treatment of MBC because of higher activity and less toxicity.

	WEEKLY PACLITAXEL-BASED COMBINATION REGIMENS IN MBC

Top Learning objectives Abstract Introduction Materials and methods Preliminary data with weekly... Weekly docetaxel in the... Weekly docetaxel in older... Weekly versus every-3-weeks... Weekly docetaxel-based... Randomized phase iii trials... Weekly paclitaxel in mbc Weekly paclitaxel in older... Weekly versus every-3-weeks... Weekly paclitaxel-based... Cross-resistance among taxanes Ongoing trials of weekly... Conclusions Disclosure of potential... References

 
The encouraging results observed in the single-agent trials evaluating weekly paclitaxel in MBC provide the basis for assessing this administration schedule in combination regimens. Weekly paclitaxel has been studied in combination with anthracyclines, platinum agents, and trastuzumab (Table 4) [74–78].

Weekly Paclitaxel–Anthracycline–Platinum Triplets
The Southern Italian Cooperative Oncology Group (SICOG) evaluated the triple combination of weekly paclitaxel, epirubicin, and cisplatin (Platinol^®; Bristol-Myers Squibb) in a series of phase I, phase II, and phase III trials [79, 80]. The phase I trial enrolled 63 women with LABC or MBC who had not received prior therapy for metastatic disease [79]. Patients received escalating doses of paclitaxel, 55 mg/m² to 120 mg/m² per week; and epirubicin, 20 mg/m² to 50 mg/m² per week; and a fixed dose of cisplatin of 30 mg/m². The ORR was 82% (95% CI, 71%–91%), with 15 complete responses. The primary DLTs were neutropenia and neuropathy. The recommended dosages used in the subsequent SICOG phase II trial were paclitaxel, 120 mg/m² per week, epirubicin, 50 mg/m² per week, and cisplatin, 30 mg/m² per week, with growth factor support [79–81]. That trial included 47 women with stage IIIB and 33 women with stage IV disease [81]. The ORR in all patients was 87% (95% CI, 76%–94%), with 21 complete responses; the ORR for the stage IIIB patients was 98%, and for the stage IV patients it was 79% [46, 81]. For the stage IIIB patients, 20 complete responses (50%), 19 partial responses (48%), and one minor response were recorded, giving a 98% response rate (95% CI, 84%–100%) [81]. Among the patients with MBC at a median follow-up of 11 months (range, 3–19 months), the median progression-free survival duration was 14 months [80]. The primary grade 3–4 toxicities observed were neutropenia, anemia, mucositis, and loss of appetite.

The results of that study encouraged the group to perform a phase III study to compare the weekly paclitaxel–epirubicin–cisplatin (PET) regimen with a standard paclitaxel–epirubicin (ET) every-3-weeks regimen in women with previously untreated LABC and MBC [82,83]. Women were randomized to receive 12 cycles of weekly PET chemotherapy (cisplatin, 30 mg/m² per week, plus epirubicin, 50 mg/m² per week, plus paclitaxel, 120 mg/m² per week, plus G-CSF) or four triweekly cycles of the ET doublet (epirubicin, 90 mg/m², plus paclitaxel, 175 mg/m²). The group reported separately the analysis of LABC [82] and MBC patients [83]. For the LABC patients, pathological complete response was the primary end point. The first analysis of the study reported on the first 140 evaluable LABC patients. Twenty complete (29%) and 41 partial (59%) responses were recorded in the PET arm, giving an 88% ORR. Eleven complete (15%) and 44 partial (62%) responses were observed in the ET arm, giving a 77% ORR. The difference between the two arms was significant for the CRR (29% versus 15%; p = .05), while there was a trend in favor of the PET arm for the ORR (88% versus 77%; p = .09). From the 130 patients that were submitted to surgery, the absence of invasive tumor in the breast (pT0+pTis) was observed in 14 and 10 patients in the PET and ET arms, respectively (p = ns). Negative axillary nodes (pN0) were found in 17 PET and 14 ET patients (p = ns). However, a complete regression of the tumor in both the breast and axilla (pT0+pTis+N0) was observed in 11 PET (16%) patients but in only three ET (4%) patients (p = .03). No differences in terms of severe neutropenia and thrombocytopenia were observed between the two arms. However, severe anemia, mucositis, peripheral neuropathy, and gastrointestinal toxicity were substantially more frequent in the PET arm.

In the analysis of MBC patients [83], the time to treatment failure was considered the main end point. An accrual of 120 patients per arm was planned, with an interim analysis on the first 60 evaluable patients of each arm. Overall, 132 patients have been recruited (64 in the PET arm and 68 in the ET arm). Of the 120 evaluable patients, 11 complete (20%) and 34 partial (60%) responses were recorded in the PET arm, giving an 80% ORR. In the ET arm, eight complete (12%) and 24 partial (38%) responses were registered, for a 50% ORR (p = .0004). At a median follow-up of 21 months, 78 failures had occurred (38 in the PET arm and 40 in the ET arm), with median times to treatment failure of 13.2 months and 14 months in the PET and ET arms, respectively (p = .97). Only 43 deaths occurred (PET, 18; ET, 25), with 4-year survival probabilities of 44% for the PET arm and 39% for the ET arm. Anemia, mucositis, peripheral neuropathy, and gastrointestinal toxicity were substantially more frequent in the PET arm. The higher toxicity, together with the lack of survival benefit, limit the use of this combination.

Randomized Phase II Studies of Weekly Paclitaxel
As a continuation of their previous phase II study testing weekly paclitaxel and carboplatin (Paraplatin^®; Bristol-Myers Squibb) in first-line MBC [84], investigators from the US Oncology group evaluated single-agent weekly paclitaxel and the combination of weekly paclitaxel and carboplatin in patients with previously untreated MBC [85]. One hundred forty-one patients were randomized to receive, on a weekly basis, paclitaxel (100 mg/m) either alone or with carboplatin with an area under the concentration–time curve (AUC) of 2. Chemotherapy was given on days 1, 8, and 15 of a 28-day cycle. About half of the patients (55%) had received prior adjuvant chemotherapy for breast cancer, and 56% of the patients were ER-positive. Patients who were HER-2 3+ by IHC or HER-2 positive by FISH were excluded. For this initial analysis, 84 patients were evaluable for response and TTP. The response rates (complete plus partial responses) were 35.0% with paclitaxel and 42.5% with the combination (p = .64). The median TTPs were 5 months with paclitaxel alone and 7.7 months with the paclitaxel–carboplatin combination (p = .054). In terms of grade 3–4 toxicities, the combination was associated with more neutropenia (38% versus 14%; p = .002). Preliminary results of this randomized phase II trial show a nonsignificant trend toward a higher response rate and longer TTP for paclitaxel and carboplatin versus paclitaxel alone.

Weekly Paclitaxel–Trastuzumab Combinations
Weekly paclitaxel plus trastuzumab was evaluated in several phase II trials involving MBC patients with HER-2–overexpressing tumors (Table 4) [86–89]. In two of the trials, patients received paclitaxel and trastuzumab weekly; one trial continued treatment until progressive disease or toxicity [86], and the other continued for 12 weeks [87]. Seidman et al. evaluated this combination in 95 patients, including 30% who had received prior treatment for MBC (Table 4) [86]. The ORR was 57%, with a complete response rate of 5%. The median response duration was 7 months. Fountzilas et al. [87] evaluated this combination as first-line therapy for MBC in 34 patients; the ORR was 62%, with a complete response rate of 12%. At a median follow-up of 14.4 months, the median TTP was 9 months [87]. In both trials, weekly paclitaxel plus trastuzumab was well tolerated, with rare grade 3–4 hematologic or nonhematologic toxicities. Seidman et al. [86] reported three cases of cardiac complications, which occurred in patients who had received prior anthracycline therapy.

A German trial evaluated the same dose of paclitaxel administered weekly in weeks 1–6 and 8–13, with trastuzumab given weekly for up to 48 weeks (Table 4) [90]. Seventy-seven MBC patients, all with anthracycline pretreatment, were enrolled. Eighty-eight percent had tumors with IHC 3+ overexpression of HER-2 (by the HercepTest^TM), with the rest being HER-2 positive by FISH. After a median duration of 24 weeks of treatment, an objective response rate of 69% was achieved, including complete remissions in 19%. Common Toxicity Criteria grade 2 toxicities were leukopenia, anemia, and peripheral neuropathy (15% of patients), and there were three cases of severe allergic reactions [90]. The question of whether the weekly paclitaxel–trastuzumab combination is superior to weekly paclitaxel was addressed by an Italian study that enrolled 89 untreated MBC patients with HER-2 overexpression (2+/3+ by HercepTest^TM) [91]. Scheduled treatment consisted of weekly paclitaxel (80 mg/m²) versus paclitaxel and trastuzumab. Both treatment arms were well tolerated. Grade 3 neuropathy was observed in 2.3% of patients in the combination arm versus 3.1% of patients in the paclitaxel alone arm; the incidences of grade 3 neutropenia were 14.2% in the combination arm and 12.5% in the paclitaxel-alone arm; no grade 4 toxicity occurred. LVEF did not decrease during the treatment in either of the arms, and no symptomatic cardiac event was observed. Sixty-two patients were evaluable for response. Somewhat surprisingly, the ORRs (70.8% versus 73.7%) and preliminary median TTPs (171 days versus 198 days) were similar in the two arms. However, the addition of trastuzumab induced a better overall response than paclitaxel alone in patients with HER-2 3+ disease (83.4% versus 62.6%) and in those with visceral disease (74.1% versus 63.2%).

To explore the activity of the paclitaxel–trastuzumab combination in anthracycline- and taxane-pretreated patients, a phase II trial was performed by an Italian group [92]. They enrolled 25 HER-2–overexpressing MBC patients in a phase II study. The treatment was planned to continue until disease progression or prohibitive toxicity; in patients with responsive or stable disease, after months of therapy, the decision to stop paclitaxel while continuing weekly trastuzumab was left to the physicians’ judgment. At a median follow-up of 19.6 months, the group reported a 16% complete response rate, a 40% partial response rate, a 16% stable disease rate, and a 28% disease progression rate. The ORR was 56% (95% CI, 36.5%–75.5%). The median TTP was 8.6 months (range, 2.5–24.2). The toxicity was mild; two patients (8%) came off study for grade 3 cardiotoxicity (after 9 weeks and 17 weeks of treatment, respectively); both had already received anthracyclines and taxanes.

In a recently published multicenter phase II trial of the Minnie Pearl Cancer Research Network, a sequential design was favored to explore several questions (Table 4) [93]. The purpose of the study was to determine the response rate of trastuzumab as first-line therapy in patients with HER-2–overexpressing MBC and to assess the feasibility and toxicity of weekly paclitaxel plus carboplatin with or without trastuzumab following initial treatment with trastuzumab. Sixty-one patients received trastuzumab (8 mg/kg followed by 4 mg/kg per week) for 8 weeks. Responding patients received eight additional weeks of trastuzumab (4 mg/kg per week), and then proceeded to receive trastuzumab (2 mg/kg) in combination with paclitaxel (70 mg/m²) and carboplatin (AUC, 2) weekly for 6 wee