Sage Journals: Discover world-class research

Abstract

Paclitaxel, a chemotherapeutic drug isolated from the Pacific yew, was approved for the treatment of metastatic breast cancer in 1994 and remains one of the most important agents in the treatment of patients with this disease. It is currently approved for the adjuvant treatment of node-positive breast cancer, administered sequentially after a standard doxorubicin-containing regimen, and for metastatic disease after failure of combination chemotherapy or relapse within 6 months of adjuvant chemotherapy. In this article, data on the pharmacology, clinical efficacy and safety of paclitaxel for the treatment of breast cancer will be reviewed.

Keywords

Abraxane™breast cancer chemotherapy docetaxel paclitaxel Taxol™Taxotere™

Breast cancer remains the most common cancer among women in the USA. Worldwide, more than a million cases will be diagnosed in 2005, with more than 50% of those patients dying of their disease [1]. Despite the increasing incidence of breast cancer, mortality rates have been decreasing due to heightened awareness, early detection and improved treatment strategies. In part, this is most likely due to the increasing use and effectiveness of adjuvant and neoadjuvant chemotherapy. Although there are many agents that have contributed to this success, the taxanes are among the most useful tools in the armamentarium to combat breast cancer. At present, the taxanes have a role in metastatic breast cancer, locally advanced breast cancer and adjuvant therapy of node-positive disease.

Taxanes in breast cancer

Although the scope of this article is the role of paclitaxel in breast cancer, this drug has many other applications. Paclitaxel is approved for use in lung cancer, ovarian cancer and Kaposi's sarcoma, and is under investigation for the treatment of a wide variety of tumors. The first report of the clinical activity of paclitaxel in metastatic breast cancer was published in 1991 [2], the benefit of paclitaxel in the adjuvant setting for node-positive breast cancer was established in the late 1990s [3,4], and the role of paclitaxel in the adjuvant treatment of lymph node-negative tumors remains under investigation. Aside from paclitaxel, there are other drugs in the taxane class that have proven efficacy in breast cancer. Docetaxel, a semisynthetic taxane from the European yew (Taxus bacatta), has demonstrated a survival benefit in the adjuvant treatment of breast cancer, as well as in the metastatic setting. In the adjuvant setting, the combination of docetaxel with doxorubicin and cyclophosphamide (TAC) improved survival when compared with fluorouracil, doxorubicin and cyclophosphamide (FAC) [5]. When compared directly with paclitaxel in patients with advanced breast cancer who had progressed after treatment with an anthracycline, docetaxel had a superior response rate, time to progression and overall survival (OS) [6]. However, as paclitaxel is more effective when scheduled weekly, which is the superior taxane remains unclear. In addition, ABI-007, a nanoparticle albumin-bound (nab) paclitaxel, is a novel, Cremophor-free paclitaxel preparation with a high therapeutic index, which does not require premedication [7]. ABI-007 has demonstrated superior efficacy to paclitaxel with fewer hematologic side effects in the metastatic setting. The role of ABI-007 in the adjuvant setting has not yet been established.

Introduction to the compound

Paclitaxel, first isolated from the bark of the Pacific yew, Taxus brevifolia, was the product of a drug-development program at the National Cancer Institute in the 1960s to evaluate the antitumor activity of natural products. It was first isolated and characterized in 1971 by Wani and colleagues in North Carolina (NC, USA) [8]. In 1977, Susan Horowitz at Albert Einstein College of Medicine (NY, USA) began to study paclitaxel's mechanism of action [9]. Although it was found to have a unique mechanism of cell-cycle arrest, the compound had many problems that delayed development. First, the compound was scarce in quantity in T. brevifolia, making isolation of large quantities difficult. Second, it had aqueous instability, leading to formulation difficulties. Finally, it was found that exposure to the Cremophor diluent frequently led to anaphylactic reactions in patients [10]. It was not until 21 years after paclitaxel's initial discovery that it was first approved by the US Food and Drug Administration (FDA) for use in ovarian cancer, and later in breast cancer. Over time, paclitaxel has proven to be one of the most effective chemotherapies in the treatment of breast cancer.

Chemistry

Paclitaxel is a diterpenoid compound with the empirical formula C₄₇H₅₁NO₁₄. The chemical structure of paclitaxel is shown in Figure 1. The side chain off carbon 13 is crucial to paclitaxel's antitumor activity, and modification of this side chain produces docetaxel. Paclitaxel is a highly lipophilic drug and is therefore insoluble in water. Due to its limited solubility, paclitaxel must be administered in a diluent of ethanol and polyethoxylated castor oil (Cremophor). The diluent is responsible for the high rate of hypersensitivity reactions observed with paclitaxel administration [11]. While the compound was originally isolated from the bark of the Pacific yew tree, paclitaxel is currently produced through a semisynthetic process, chemically altering 10-deacetylbaccatin-III to form paclitaxel in the laboratory [12].

Figure 1.

Paclitaxel.

Mechanisms of action & resistance

The main antitumor effect of paclitaxel is derived from the compound binding the β-sub-unit of tubulin, causing polymerization of microtubules, preventing normal mitotic spindle formation, leading to cell-cycle arrest in the G₂/M phase and triggering the mitochondrial activation of the pathways of apotosis. Paclitaxel, docetaxel and ABI-007 have been deemed the microtubule-targeted tubulin-polymerizing agents (MTPAs). By binding β-tubulin and causing microtubule polymerization, they prohibit the normal dynamic function of microtubules during mitosis [13].

The best described mechanism of resistance is the increased expression of the multidrug resistance (MDR) gene [14]. Overexpression of this gene, belonging to the ATP-binding cassette (ABC) superfamily, results in increased synthesis of membrane P-glycoprotein, which acts as an efflux pump and prevents the action of a variety of chemotherapy agents, including vinka alkaloids, anthracyclines and taxanes [15]. The family of ABC multidrug transporters, which consists of nine members, has many important roles in paclitaxel resistance. Generally, they may act by increasing drug efflux, decreasing drug uptake, recruiting drug-processing and -metabolizing enzymes, changing the activity of conjugating enzymes, altering DNA repair activity and reducing cell susceptibility to apoptosis [16]. P-glycoprotein (ABCB1), motility-related protein (MRP)-1 (ABCC1) and breast cancer-resistance protein (ABCG2) can make tumor cells resistant to various chemotherapies and decrease their oral absorption. MRP-2 (ABCC2) also limits oral availability and has been found to increase hepatobiliary and intestinal excretion [17]. Multidrug MDR protein 7 (ABCC10) has also recently been shown to serve as an efflux pump for paclitaxel [18]. Overcoming the actions of the ABC transporters is an area of ongoing research. Tubulin mutations may also play a role in drug resistance [19].

Pharmacokinetics & metabolism

Paclitaxel distribution and elimination is largely dependent on the diluent used in administration, and different formulations of paclitaxel therefore exhibit different pharmacokinetic properties. For example, the total-body clearance and volume of distribution of ABI-007 were 50% higher than paclitaxel suspended in Cremophor, suggesting that the Cremophor prevents the distribution of paclitaxel out of the circulation and into tissues [20]. The pharmacokinetic properties of paclitaxel suspended in Cremophor are outlined in Box 1. The plasma concentrations of paclitaxel decline rapidly after intravenous infusion is complete [21]. The metabolism of paclitaxel is predominantly hepatic, utilizing the cytochrome (CYP)450 enzymes, CYP2C8 and CYP3A4. Elimination is via hepatic detoxification and biliary excretion, with only a fraction of the drug in its unchanged form cleared by renal or fecal excretion [22]. Dose adjustment in patients with hepatic dysfunction is important [23]. Paclitaxel has drug interactions with anthracyclines and cisplatin, and other formulations of paclitaxel can interact with drugs that compete with its metabolism or activate a MDR pump. The drug interaction with anthracyclines causes cardiotoxicity, an important consideration, as they are often given together. When paclitaxel precedes doxorubicin, the clearance of doxorubicin is reduced and an increase in cardiotoxicity is seen. Cardiotoxicity can be minimized by administering doxorubicin first and separating the drugs by more than 1 h [24]. When paclitaxel is administered following cisplatin, the clearance of paclitaxel is decreased by 33%.

Box 1.

Pharmacokinetic properties of paclitaxel.

Pharmacokinetics

Nonlinear

Protein binding

95–98%

Metabolism

Hepatic via cytochrome P (CYP)450 enzymes CYP2C8 and CYP3A4

Elimination

Primarily hepatic detoxification and biliary excretion, 5% renal

Drug interactions

Doxorubicin and others

Clinical efficacy

Phase I studies

Phase I trials of paclitaxel demonstrated many tolerable doses and administration schedules (Table 1) [25]. The maximum tolerated dose for paclitaxel given over 3 h was 250 mg/m², over 24 h it was 225 mg/m², and for 96-h administration it was 140 mg/m² [26 –28]. Although the Phase I studies of paclitaxel did not clarify an optimal treatment dose, they did elucidate important knowledge regarding its administration. In early trials, hypersensitivity reactions, which could be life-threatening, were common, occurring in 18% of patients receiving paclitaxel at 15–160 mg/m² over a 3-h infusion and 60% of patients receiving higher doses (190–230 mg/m²) over a 3-h infusion [29]. Hypersensitivity reactions were later understood to be largely a function of the Cremophor diluent and preventable with longer infusion times and premedication with steroids and histamine blockade. As the diluent is largely responsible for these reactions, it is reasonable to expect that hypersensitivity reactions would be minimized with other formulations of the drug. For example, studies of ABI-007 have shown no severe hypersensitivity reactions [30,31]. However, mild hypersensitivity reactions have been observed with ABI-007, suggesting that some of these reactions may be mediated by paclitaxel and are not entirely explainable by the Cremophor solvent.

Table 1.

Phase I studies of paclitaxel.

Year	Duration of infusion (h)	Number of patients	Phase II dose recommendation	Dose-limiting toxicity	Ref.
1987	1–6	34	250 mg/m²/1–6 h	Neutropenia	[21]
1994	3	35	250 mg/m²/3 h	Myelosupression	[26]
1987	24	26	250 mg/m²/24 h	Neuropathy	[27]
1994	96	12	140 mg/m²/96 h	Neutropenia Mucocitis	[28]
1986	3	17	190 mg/m²/3 h	Hypersensitivity	[29]
1986	1	20	30 mg/m² × 5 days	Neutropenia	[57]
1987	1–6	16	30 mg/m² × 5 days	Neutropenia	[58]
1987	1–6	30	212 mg/m²/1–6 h 170 hg/m² in heavily pretreated patients	Neutropenia	[59]
1991	6	31	225 mg/m²/6 h	Neutropenia	[60]
1989	24	17	310 mg/m²/24 h	Mucositis	[61]
1992	24	15	250 mg/m²/24 h	Neuropathy	[62]
1993	24	31	350 mg/m²/24 h	Neurotoxicity	[63]
1992	120	20	150 mg/m²/20 h	Neutropenia	[64]

Phase II studies

Due to the lack of optimal dose to pursue in Phase II studies, paclitaxel doses varied largely in subsequent trials, with considerable controversy over the optimal dose and scheduling (Table 2). When a 3-h infusion time was compared with a 24-h infusion time, both treatment arms had similar time to progression, but more toxicity was observed with longer infusions [32]. In the registration trial, paclitaxel 135 mg/m² was compared with 175 mg/m², with response rates of 22 and 29%, respectively (p = not significant). These studies led to the approval of paclitaxel 175 mg/m² over 3 h for breast cancer treatment [33]. Although subsequent studies with higher doses or longer infusion schedules suggested higher response rates, no survival benefit was apparent and toxicity was substantially increased [34 –36]. A randomized Phase III study has since confirmed that increasing doses of paclitaxel are not associated with improved response rates or survival in patients with metastatic breast cancer [34]. More recent studies have evaluated the role of weekly paclitaxel, where an optimal dose appears to be 80 mg/m² [37]. In a relatively heavily pretreated population of patients with metastatic breast cancer, 21.5% of patients responded and 41.8% had disease stabilization [37]. Therapy was well tolerated, with the most significant toxicities being a 15% incidence of grade 3 or 4 hematologic toxicity and a 9% incidence of grade 3 neurotoxicity.

Table 2.

Phase II studies of paclitaxel.

Year	Number of patients	Stage	Pretreated	Dose and schedule	ORR	TTP (p)	OS	Ref.
1991	25	IV	23/25	250 mg/m²/3 h	23 (NS)	NA	11 (NS)	[2]
1995	521	Advanced	2/3	175 mg/m²/3 h 175 mg/m²/24 h	29 (NS) 31	NS	NA	[32]
1996	471	IV	Ye s	135 mg/m²/3 h 175 mg/m²/3 h 140 mg/m²/96 h	22 (p = 0.108) 29 29	3 (p = 0.03) 4.2	10.5 (p = 0.321) 11.7 10	[33]
2004	474	IV	76% yes	175 mg/m²/3 h 210 mg/m²/3 h 250 mg/m²/3 h	23 (NS) 26 21	3.9 (0.45) 4.1 4.9	11(0.3) 12 14	[34]
1999	563	IIIB and IV	53% yes	250 mg/m²/3 h 250 mg/m²/24 h	41 (p = 0.025) 51	NA	NA	[35]
2001	212	IV	90% yes	80 mg/m²/h	21.5	4.7	12.8	[37]

NA: Not available; NS: Not significant; ORR: Overall response rate; OS: Overall survival; TTP: Time to progression.

Phase III studies in metastatic breast cancer

Paclitaxel was then studied in the first-line metastatic setting against the most active current regimens. When compared with cyclophosphamide, methotrexate, 5-fluorouracil and prednisone (CMFP), paclitaxel resulted in similar response rates and survival, although this study was underpowered to detect survival differences [38]. Two studies compared paclitaxel with doxorubicin, with somewhat conflicting results. The American Intergroup study showed comparable efficacy between doxorubicin 60 mg/m² and paclitaxel 175 mg/m², but the European Organisation for Research and Treatment of Cancer (EORTC) study reported that doxorubicin 75 mg/m² had higher response rates and longer time to progression than paclitaxel 200 mg/m² [39,40]. Patient selection or unknown biases may account for these differences. A summary of Phase III studies can be seen in Table 3.

Table 3.

Phase III studies of paclitaxel for metastatic breast cancer.

Year	N	Setting	Prior chemotherapy (%)	Drug/dose	ORR	TTP/duration of response (months)	OS	Ref.
2003	739	Front-line metastatic	41	Paclitaxel 175 mg/m²/24 h	34 (p = 0.84)	5.8 (p < 0.68)	18.9 (NS)	[39]
				Doxorubicin 60 mg/m²	36	6	22.2
				Paclitaxel 150 mg/m²/24 h Doxorubicin 50 mg/m²	47 (p = 0.04; p = 0.07)	8 (p = 0.009; p = 0.003)	22
1999	209	Front-line metastatic	27	Paclitaxel175 mg/m²/3 hCMFP	29 (p = 0.37)35	5.3 (p = 0.25)6.4	17.3(p = 0.025)13.9	[38]
2000	331	Front-line metastatic	33	Paclitaxel200 mg/m²/3 h	25(p = 0.003)	7.7	15.6 (NS)	[40]
				Doxorubicin 75 mg/m²	41	9.7	18.3

CMFP: Cyclophosphamide, methotrexate, 5-fluorouracil and prednisone; NS: Not significant; ORR: Overall response rate; OS: Overall survival; TTP: Time to progression.

Considerable effort has continued to be invested in finding the optimal scheduling of paclitaxel, with weekly administration holding particular promise. The Cancer And Leukemia Group B (CALGB) 9840 trial compared weekly paclitaxel 80 mg/m² over a 1-h infusion with 3-weekly paclitaxel 175mg/m² over a 3-h infusion. The weekly administration schedule demonstrated a significant benefit in overall response rate (40 vs 28%, p = 0.017), time to progression (9 vs 5 months, p = 0.0008) and had a nonstatistically significant trend toward superior OS (24 vs 16 months, p = 017) [41]. This study suggests that paclitaxel is most effective when given weekly. However, the validity of this trial has been questioned as, in an effort to gain statistical power, it included patients treated in another CALGB study and thus was not truly randomized.

As taxanes demonstrate their efficacy in the metastatic setting, questions of the superior taxane are often raised, and a comparative efficacy and toxicity profile is shown in Table 4. Paclitaxel and docetaxel have been directly compared in the metastatic breast cancer setting among patients treated with prior anthracycline therapy [6]. In the Phase III study, paclitaxel 175 mg/m² was compared with docetaxel 100 mg/m² every 21 days. Overall response rates were 25% in the paclitaxel arm versus 32% in the docetaxel arm (p = 0.1), with time to progression of 3.6 versus 5.7 months (p = 0.001) and an OS of 12.7 versus 15.4 months (p = 0.03), respectively. However, the relative dose of docetaxel was higher than that of paclitaxel, and the hematologic and nonhematologic toxicities were substantially higher in the docetaxel arm.

Table 4.

Paclitaxel every 3 weeks compared with docetaxel, ABI-007 and weekly paclitaxel.

Drug	Dose	ORR (%)	TTP (months)	OS (months)	Neutropenia grade 3/4 (%)	Febrile neutropenia (%)	Neuropathy grade 3/4 (%)	Ref.
Paclitaxel	175 mg/m² every 21 days	19	3.9	12.9	22†	<2	2	[1]
ABI-007	260 mg/m² every 21 days	33	5.3	15*	9†	<2	10
Paclitaxel	175 mg/m² every 21 days	25	3.6		55	2	6	[6]
Docetaxel	100 mg/m² every 21 days	32	5.1		93	15	12
Paclitaxel	175 mg/m² every 21 days	28	5	16	15	4‡	16	[41]
Paclitaxel	80 mg/m² every 7 days	40	9	24*	5	3‡	31

p: NS

†

Grade 4 only

‡

Infection.

NS: Not significant; ORR: Overall response rate; OS: Overall survival; TTP: Time to progression.

ABI-007 has also demonstrated superior efficacy to paclitaxel in a Phase III study. In this study, 454 patients were assigned to ABI-007 260 mg/m² every 3 weeks or paclitaxel 175 mg/m² every 3 weeks. Patients in the ABI-007 arm had a superior response rate and time to tumor progression (33 vs 19%, p = 0.001; 23 vs 16.9 weeks, p = 0.006), with less neutropenia. Grade 3 sensory neuropathy occurred in 10% of patients treated with ABI-007 versus 2% of patients treated with paclitaxel. However, the neuropathy recovered quickly, in a median of 22 days, so the clinical significance is unclear [31]. Given that Phase III studies have not directly compared weekly paclitaxel with docetaxel or ABI-007, the optimal taxane remains unclear, and each remains a reasonable therapeutic option for women with metastatic breast cancer.

Another important issue in the treatment of metastatic breast cancer with paclitaxel is the role of combination versus sequential chemotherapy. In a study led by the Eastern Cooperative Oncology Group (ECOG), paclitaxel alone was compared with doxorubicin alone and with the combination of paclitaxel and doxorubicin [39]. When patients treated with single agents progressed, they crossed over to the alternate single agent. Although the patients treated with combination therapy had higher response rates, OS did not differ between the three study arms. In addition, concerns over the potential cardiotoxicity of paclitaxel and anthracycline combinations have limited the use of this therapy. More recent studies have studied paclitaxel in combination with other chemotherapeutic agents, such as gemcitabine, but whether sequential or combination therapy is superior has not been established [42 –44].

Paclitaxel combinations with newer biologic agents have shown more promise. These agents used in combination with traditional chemotherapy have an application in the metastatic setting and warrant investigation in the adjuvant setting. In the pivotal trastuzumab trial for metastatic breast cancer, the combination of paclitaxel and trastuzumab produced superior response rates and OS than paclitaxel alone [45]. A recent study showed that bevacizumab, a monoclonal antibody against vascular endothelial growth factor, improves response rate, time to progression and trend towards OS in patients with metastatic or locally recurrent breast cancer when given with paclitaxel [46]. These studies suggest an important future role for paclitaxel in combination with biologic agents.

Phase III adjuvant studies

After the efficacy of paclitaxel was demonstrated in the metastatic setting, trials were initiated to determine its efficacy in the adjuvant setting. CALGB 9344 was the first randomized trial to evaluate the impact of paclitaxel on the survival of women with lymph node-positive breast cancer [4]. This study randomized patients with node-positive breast cancer to receive one of three doses of doxorubicin as part of four cycles of doxorubicin and cyclophosphamide (AC), followed by either no further therapy or four cycles of paclitaxel 175 mg/m². The hazard reductions with the addition of paclitaxel were 17% for recurrence (p = 0.0023) and 18% for death (p = 0.0064). At 5 years, the disease-free survival (DFS) was 70% in the paclitaxel-containing arm versus 65% in the nonpaclitaxel-containing arm, and OS was 80 and 77%, respectively. The results of CALGB 9344 were first presented in May 1998 and led to the approval of paclitaxel for the adjuvant treatment of node-positive breast cancer in 1999 (Figure 2). Of note, in an unplanned subset analysis, the benefit of paclitaxel appeared to be primarily in patients with estrogen receptor (ER)-negative breast cancer. This finding was further evaluated in an analysis of over 6000 patients treated over the past 20 years in CALGB trials, which showed that adjuvant chemotherapy had a consistently greater impact on patients with ER-negative disease [47].

Figure 2.

FDA approved indications for paclitaxel.

In 2000, the results of the National Surgical Adjuvant Breast and bowel Project (NSABP)-B28 trial were initially presented, which also showed a benefit for paclitaxel after a standard anthracycline regimen [3]. NSABP B-28 enrolled 3060 women with node-positive breast cancer and randomized them to treatment with four cycles of AC versus four cycles of AC followed by followed by four cycles of paclitaxel. This trial demonstrated a significant improvement in DFS: 76% in the paclitaxel arm versus 72% in the control arm. However, at 5 years follow-up, there was no significant improvement in OS. These discrepant findings may be due to a higher proportion of ER-positive patients in the NSABP study, concomitant use of tamoxifen with chemotherapy or chance. It should be noted that both the CALGB and the NSABP study had an important limitation, in that they compared patients treated with unequal duration of chemotherapy (eight vs four cycles). Therefore, the benefits observed could be due to either the addition of paclitaxel or longer duration of chemotherapy.

Weekly paclitaxel has been studied in a smaller Phase III neoadjuvant study. Patients were randomized to weekly paclitaxel for 12 weeks versus paclitaxel given every 3 weeks for four cycles [48]. In both treatment arms, paclitaxel was followed by four cycles of FAC. Patients treated on the weekly schedule had a pathologic complete response (pCR) rate of 28.2% compared with 15.7% of patients treated on the 3-weekly schedule (p = 0.02) [48]. In addition, patients treated on the weekly paclitaxel arm had increased rates of breast conservation.

There are many ongoing studies designed to answer questions regarding the optimal taxane, dosing schedule and role of combination therapies. ECOG 1199 is an ongoing adjuvant study to compare weekly versus 3-weekly paclitaxel and docetaxel in node-positive and -negative breast cancer. This study randomized patients to one of four arms after four courses of AC: weekly paclitaxel for 12 weeks, weekly docetaxel for 12 weeks, 3-weekly paclitaxel for four cycles, or 3-weekly docetaxel for four cycles. The NSABP B-28 is an ongoing trial for node-positive patients that compares three adjuvant therapies: TAC for six cycles, dose-dense AC for six cycles followed by dose-dense paclitaxel, and dose-dense AC for six cycles followed by dose-dense paclitaxel plus gemcitabine. Other studies are investigating the role of paclitaxel in node-negative breast cancer. CALGB 40101 randomized high-risk, node-negative patients to dose-dense AC for four cycles, dose-dense AC for six cycles, paclitaxel every 2 weeks for four cycles and paclitaxel every 2 weeks for six cycles. These and other ongoing studies will help to clarify the optimal use of adjuvant taxanes.

One of the most exciting developments in the adjuvant treatment of breast cancer has been the recent reports of the dramatic benefits of adjuvant trastuzumab, given concurrently with or after paclitaxel, among women with human epidermal growth factor receptor type 2 (HER2)-overexpressing breast cancer [49]. Two large, multicenter trials compared patients treated with chemotherapy with patients treated with chemotherapy plus 1 year of trastuzumab. These trials were based on the preclinical studies that demonstrated synergistic effects between taxanes and trastuzumab, as well as previous studies in the metastatic setting [45,50]. The NSABP B-31 trial randomized patients to AC followed by 3-weekly paclitaxel or the same regimen plus 52 weeks of trastuzumab. Trastuzumab was initiated with the first dose of paclitaxel. The North Central Cancer Treatment Group (NCCTG) N9831 trial compared three regimens: AC followed by weekly paclitaxel, the same regimen plus 52 weeks of trastuzumab initiated after completion of paclitaxel, and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel. The studies were combined for analysis, with the control arm consisting of the nontrastuzumab regimens and the experimental arm combining the two regimens in which trastuzumab was administered concurrently with paclitaxel. Although these results are early, the findings were dramatic. Patients treated with trastuzumab had a 12% absolute benefit in DFS at 3 years. Trastuzumab therapy was associated with a 33% reduction in the risk of death (p = 0.015). A second analysis was performed on the patients in the N9831 study, comparing those patients treated concurrently with paclitaxel and trastuzumab with those treated sequentially. Those patients treated with concurrent paclitaxel and trastuzumab had a 36% lower risk of recurrence than those treated sequentially (p = 0.011). These studies demonstrate that adjuvant trastuzumab with chemotherapy is the new standard for women with HER2-overexpressing breast cancer and suggest that concurrent paclitaxel and trastuzumab may the the most effective regimen.

Safety & tolerability

Hypersensitivity reactions

In early clinical trials, one third of patients developed major hypersensitivity reactions to paclitaxel characterized by urticaria, hypotension, dyspnea and angioedema. Eventually, it was determined that these reactions were primarily due to the Cremophor suspension [10]. However, with the administration of steroids and histamine blockade, these hypersensitivity reactions can be prevented and now only occur in 2–5% of patients [31,48,51]. Premedication with histamine blockade and steroids is now considered the standard of care.

Neutropenia

Neutropenia is a serious dose-limiting toxicity of paclitaxel administration and appears to be directly related to dose and the length of infusion time. Patients begin to have falling white blood cell counts on days 5–7, nadir between days 7–14, and generally recover by days 15–21. Many trials have supported patients with granulocyte colony-stimulating factor (G-CSF) to prevent infectious complications related to neutropenia. The maximal tolerated dose without G-CSF support is 175–200 mg/m² [10]. Granulocytopenia is more common with a 3-weekly dosing schedule.

Neurotoxicity

Neurosensory toxicity is another common side effect of paclitaxel, typically characterized by a burning pain or numbness and tingling of the extremities in a stocking–glove distribution [52]. Symptoms typically appear as the cumulative dose increases and are directly related to dose. These symptoms often do not resolve after paclitaxel therapy is stopped and can become chronic for months or years. Paclitaxel-induced neuropathy is difficult to treat and resistant to opiods. Ethosuximide has demonstrated reversal of mechanical allodynia/hyperalgesia and may have a role in treatment [53]. Neuromotor toxicity also occurs. Neurotoxicity is more common with the weekly dosing schedule. Generalized myalgia is also common.

Cardiotoxicity

The cardiotoxicity of paclitaxel manifests as conduction disturbances, typically effecting the Purkinje system or extracardiac autonomic control [54]. Transient asymptomatic bradycardia is reported in up to 29% of patients. Heart block is an uncommon side effect.

Others

Other side effects include reversible alopecia, asthenia/fatigue, rash, gastrointestinal toxicity, extravasation injury and radiation recall. Radiation recall is a phenomenon seen with both paclitaxel and docetaxel.

Regulatory affairs

Paclitaxel was approved for use in metastatic breast cancer in the USA in 1994, and an FDA approval timeline is represented in Figure 2. Currently, paclitaxel is approved in the USA for metastatic breast cancer, disease that has relapsed within 6 months of adjuvant therapy and adjuvant therapy of lymph node-positive breast cancer. In addition to its role in breast cancer, paclitaxel is FDA-approved for the treatment of AIDS-related Kaposi's sarcoma (second-line), non-small cell lung cancer in combination with cisplatin in patients who are not candidates for surgery or radiation, and in the treatment of ovarian cancer. Paclitaxel is now widely used throughout the world in the treatment of these tumors. Less commonly, paclitaxel is used in the treatment of other tumor types. Paclitaxel also has a role in paclitaxel-eluting stents for use in the prevention of restenosis in coronary artery disease [55].

Conclusion

Paclitaxel has demonstrated antitumor activity in metastatic breast cancer. Paclitaxel decreases the risk of cancer recurrence and improves OS in the adjuvant setting for patients with node-positive disease. While initial Phase I–II studies suggested that paclitaxel 175 mg/m² every 3 weeks was an optimal dose, more recent studies suggest that weekly dosing at 80 mg/m² is more effective. Other taxane formulations, such as docetaxel and ABI-007, have also demonstrated efficacy in the metastatic setting. Newer combinations of drugs with paclitaxel are improving the treatment of breast cancer further.

Future perspective

The last few decades have led to much improvement in the treatment and survival of breast cancer patients. The movement of taxanes in the treatment of breast cancer from the metastatic to the adjuvant and neoadjuvant settings has improved outcomes. Many new formulations of paclitaxel are under development, with the hope of increasing efficacy and reducing toxicity. These include an oral paclitaxel, polyglutamated paclitaxel and formulations using emulsions, stabilized emulsions with soluble polymers, liposomes and diblock copolymer micelles. ABI-007 has recently been approved in the USA, with superior response rates and decreased risk of hypersensitivity reactions. An additional class of drugs, the epothilones, is under development. The epothilones are microtubule-stabilizing agents that have activity in taxane-sensitive and -resistant disease and are currently being tested in Phase III trials for metastatic breast cancer [56]. These agents may provide an additional option for women with taxane-resistant breast cancer. Paclitaxel in combination with biologic agents, such as antibodies and small molecules, is one of the most promising areas of development. In addition, as we learn that breast cancer is not one but many diseases that each has a unique signature, patient-specific therapies may maximize benefit for susceptible patients while limiting toxicity in those who would not benefit.

Executive summary

Mechanism of action

Paclitaxel binds the β-subunit of tubulin, causing polymerization of microtubules.

It prevents normal mitotic spindle formation.

It causes cell cycle arrest in the G₂/M phase.

It induces apoptosis.

Pharmacokinetic properties

Pharmakokinetic properties regarding volume of distribution and clearance are highly variable and largely dependent on the diluent used in administration.

Paclitaxel is highly lipophilic.

Its metabolism is predominantly hepatic, utilizing cytochrome (CYP)450 enzymes, CYP2C8 and CYP3A4.

The renal excretion of the unchanged drug also plays a role in the elimination of paclitaxel.

In patients with hepatic insufficiency, dose reductions are recommended.

Clinical efficacy

Paclitaxel has demonstrated efficacy at 175 mg/m² in metastatic breast cancer, recurrent breast cancer and node-positive breast cancer.

Paclitaxel has demonstrated superior efficacy using a weekly administration schedule of 80 mg/m² in these settings, but is not approved by the US Food and Drug Administration for this dose.

Safety & tolerability

Paclitaxel is associated with hypersensitivity reactions in patients without premedication, which can largely be avoided with the use of steroids and histamine blockade.

Neutropenia is a dose-limiting toxicity at the approved dose and can be minimized with shorter infusion times and granulocyte colony-stimulating factor support.

Peripheral neuropathy is a common cumulative toxicity, particularly with weekly scheduling.

Interactions with cisplatin and doxorubicin are well documented. Concerns of interactions with drugs that are similarly metabolized or activate the multidrug resistance pump exist.

Dosage & administration

Paclitaxel is approved at 175 mg/m² every 3 weeks.

It has superior efficacy at 80 mg/m² weekly dosing.

Premedication with steroids and histamine-blocking agents is considered the standard of care when administering paclitaxel, to decrease the incidence of hypersensitivity reactions.

References

Jemal

Murray

Ward

: Cancer Statistics, 2005. CA Cancer J. Clin. 55(1), 10–30 (2005).

Holmes

Theriault

: Phase II trial of taxol an active drug in the treatment of metastatic breast cancer. J. Natl Cancer Inst. 83, 1797–1805 (1991).

Mamounas

Bryant

Lembersky

: Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J. Clin. Oncol. 23(16), 3686–3696 (2005).

Henderson

Berry

Demetri

: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J. Clin. Oncol. 21(6), 976–983 (2003).

Martin

Pienkowski

Mackey

: Adjuvant docetaxel for node-positive breast cancer. N. Engl. J. Med. 352(22), 2302–2313 (2005).

Jones

Erban

Overmoyer

: Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J. Clin. Oncol. 23(24), 5542–5551 (2005).

Blum

Savin

Edelman

: Long-term disease control in taxane-refractory metastatic breast cancer treated with nab paclitaxel. J. Clin. Oncol. 22(145), 543 (2004).

Wani

Taylor

Wall

: Plant antitumour agents VI. The isolation and structure of taxol, a novel antileukemic and antitumour agent agent from Taxus brevifolia. J. Am. Chem. Soc. 93, 2325–2327 (1971).

Horwitz

: Personal recollections on the early development of taxol. J. Nat. Prod. 67(2), 136–138 (2004).

10.

Rowinsky

Donehower

: Drug therapy: paclitaxel. N. Engl. J. Med. 332, 1004–1014 (1995).

11.

Szebeni

Muggia

Alving

: Complement activation by cremophor EL as a possible contributor to hypersensitivity to paclitaxel: an in vitro study. J. Natl Cancer Inst. 90, 300–306 (1998).

12.

Verweij

Clavel

: Paclitaxel (Taxol) and docetaxel (Taxotere): not simply two of a kind. Ann. Oncol. 5(6), 495–505 (1994).

13.

Bhalla

: Microtubule-targeted anticancer agents and apoptosis. Oncogene 22, 9075–9086 (2003).

14.

Dumontet

Sikic

: Mechanisms of action of and resistance to antitubulin agents: microtubule dynamics, drug transport, and cell death. J. Clin. Oncol. 17(3), 1061–1070 (1999).

15.

Brooks

Minderman

O'Loughlin

: Taxane-based reversal agents modulate drug resistance mediated by P-glycoprotein, multi-drug resistance protein, and breast cancer resistance protein. Mol. Cancer Ther. 2(11), 1195–1205 (2003).

16.

Annereau

Stzakacs

Tucker

: Analysis of ATP-binding cassette transporter expression in drug-selected lines by a microarray dedicated to multi-drug resistance. Mol. Pharmacol. 66, 1397–1405 (2004).

17.

Huisman

Chhatta

Tellingen

: MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid. Int. J. Cancer 116(5), 824–829 (2005).

18.

Hopper-Borge

Chen

Shchaveleva

: Analysis of the drug resistance profile of multi-drug resistance protein 7 (ABCC10): resistance to docetaxel. Cancer Res. 64(14), 4927–4930 (2004).

19.

Cabral

Brady

Schibler

: A mechanism of cellular resistance to drugs that interfere with microtubule assembly. Ann. NY Acad. Sci. 466(1), 745–756 (1986).

20.

Sparreboom

Scripture

Trieu

: Comparative preclinical and clincal pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in cremophor (Taxol). Clin. Cancer Res. 11(11), 4136–4143 (2005).

21.

Wiernik

Schwartz

Strauman

Dutcher

Lipton

Paietta

: Phase I clinical and pharmacokinetic study of taxol. Cancer Res. 47(9), 2486–2493 (1987).

22.

Center for Drug Evaluation and Research (CDER), US Food and Drug Administration (FDA): Guidance for Industry: Labeling Guidance for Paclitaxel Injection. CDER and FDA, USA (1997).

23.

Seidman

Hochhauser

Gollub

: Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: a Phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer. J. Clin. Oncol. 14(6), 1877–1884 (1996).

24.

Gligorov

Lotz

: Preclinical pharmacology of the taxanes: implications of the differences. Oncologist 9(Suppl. 2), 3–8 (2004).

25.

Nabholtz

Gilgorov

: The role of taxanes in the treatment of breast cancer. Expert Opin. Pharmacother. 6(7), 1073–1094 (2005).

26.

Schiller

Storer

Tutsch

: A Phase I trial of 3-hour infusions of paclitaxel (Taxol) with or without granulocyte colony-stimulating factor. Semin. Oncol. 5(Suppl. 8), 9–14 (1994).

27.

Wiernik

Schwartz

Einzig

: Phase I trial of taxol given as a 24-hour infusion every 21 days: responses observed in metastatic melanoma. J. Clin. Oncol. 5(8), 1232–1239 (1987).

28.

Wilson

Berg

Bryant

: Paclitaxel in doxorubicin-refractory or mitoxantrone-refractory breast cancer: a Phase I/II trial of 96-hour infusion. J. Clin. Oncol. 12(8), 1621–1629 (1994).

29.

Kris

O'Connell

Gralla

: Phase I trial of taxol given as a 3-hour infusion every 21 days. Cancer Treat. Rep. 70(5), 605–607 (1986).

30.

Micha

Goldstein

Birk

: Abraxane in the treatment of ovarian cancer: the absence of hypersensitivity reactions. Gynecol. Oncol. (2005) (Epub ahead of print).

31.

Gradishar

Tjulandin

Davidson

: Superior efficacy of albumin-bound paclitaxel, ABI-007, compared with polyethylated castor oil-based paclitaxel in women with metastatic breast cancer: results of a phase III trial. J. Clin. Oncol. 23(31), 7794–7803 (2005).

32.

Peretz

Sulkes

Chollet

: A multicenter, randomized study of two schedules of paclitaxel in patients with advanced breast cancer. Eur. J. Cancer 31(Suppl. 5) S75 (1995).

33.

Nabholtz

Gelmon

Bontenbal

: Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J. Clin. Oncol. 14(6), 1858–1867 (1996).

34.

Winer

Berry

Woolf

: Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: cancer and leukemia group B trial 9342. J. Clin. Oncol. 22(11), 2061–2068 (2004).

35.

Smith

Brown

Mamounas

: Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26. J. Clin. Oncol. 17(11), 3403–3411 (1999).

36.

Holmes

Valero

Buzdar

: Final results: randomized Phase II trial of paclitaxel by 3-hr versus 96-hr infusion in patients with met breast cancer. The long and short of it. Proc. Am. Soc. Clin. Oncol. (1998) (Abstract 426).

37.

Perez

Vogel

Irwin

: Multicenter Phase II trial of weekly paclitaxel in women with metastatic breast cancer. J. Clin. Oncol. 19(22), 4216–4223 (2001)

38.

Bishop

Dewar

Toner

: Initial paclitaxel improves outcome compared with cmfp combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J. Clin. Oncol. 17(8), 2355–2364 (1999).

39.

Sledge

Neuberg

Bernardo

: Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an Intergroup Trial (E1193). J. Clin. Oncol. 21(4), 588–592 (2003).

40.

Paridaens

Biganzoli

Bruning

: Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European organization for research and treatment of cancer randomized study with cross-over. J. Clin. Oncol. 18(4), 724–733 (2000).

41.

Seidman

Berry

Cirrincione

: CALGB 9840: Phase III study of weekly paclitaxel via 1-hour infusion versus standard 3h infusion every third week in the treatment of metastatic breast cancer, with trastuzumab for HeR2 positive MBC and randomized for T in HeR2 normal MBC. Proc. Am. Soc. Clin. Oncol. 22, 6 (2004) (Abstract 512).

42.

Murad

Guimares

Aragao

Scalabrini-Neto

Rodrigues

Garcia

: Phase II trial of the use of paclitaxel and gemcitabine as a salvage treatment in metastatic breast cancer. Am. J. Clin. Oncol. 24, 264–268 (2001).

43.

Khoo

Zaidi

Srimuninnimit

: Randomized Phase II trial of three gemcitabine (GEM)-taxane combinations in metastatic breast cancer (MBC). Proc. Am. Soc. Clin. Oncol. 23(Suppl. 54) S54 (2004) (Abstract 710).

44.

Colomer

Lluch

: Biweekly paclitaxel and gemcitabine in advanced breast cancer: Phase II trial and predictive value of HER2 extracellular domain. Ann. Oncology 15, 201–206 (2004).

45.

Slamon

Leyland-Jones

Shak

: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344(11), 783–792 (2001).

46.

Miller

Wang

Gralow

: A randomized Phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer. Proc. Am. Soc. Clin. Oncol. 23(16), S19 (2005) (Abstract 563).

47.

Berry

Cirrincione

Henderson

: Effects of improvements in chemotherapy on disease-free and overall survival of estrogen receptor negative, node positive breast cancer: 20-year experience of the CALGB and US Breast Intergroup. Breast Cancer Res. Treat. 88 (2004).

48.

Green

Buzdar

Smith

: Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J. Clin. Oncol. 23(25), 5983–5992 (2005).

49.

Piccart-Gebhart

Procter

Leyland-Jones

: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N. Engl. J. Med. 353(16), 1659–1672 (2005).

50.

Pegram

Hsu

Lewis

: Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 18(13), 2241–2251 (1999).

51.

Weiss

Donehower

Wiernik

: Hypersensitivity reactions from taxol. J. Clin. Oncol. 8(7), 1263–1268 (1990).

52.

Rowinsky

Eisenhauer

Chaudhry

: Clinical toxicities encountered with paclitaxel (Taxol). Semin. Oncol. 20(Suppl. 3), 1–15 (1993).

53.

Flatters

Bennet

: Ethosuximide reverses pacltiaxel- and vincristine-induced painful peripheral neuropathy. Pain 109, 150–161 (2004).

54.

McGuire

Rowinsky

Rosenshein

: Taxol: a unique antineoplastic agent with significant activity in advancedovarian epithelial neoplasms. Ann. Intern. Med. 111, 273–279 (1989).

55.

Stone

Ellis

Cannon

: Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease: a randomized controlled trial. JAMA 294(10), 1215–1223 (2005).

56.

Low

Wedam

Lee

: Phase II clinical trial of ixabepilone (BMS-247550), an epothilone b analog, in metastatic and locally advanced breast cancer. J. Clin. Oncol. 23(12), 2726–2734 (2005).

57.

Legha

Tenney

Krakoff

: Phase I study of taxol using a 5-day intermittent schedule. J. Clin. Oncol. 4(5), 762–766 (1986).

58.

Grem

Tutsch

Simon

: Phase I study of taxol administered as a short iv. infusion daily for 5 days. Cancer Treat. Rep. 71(12), 1179–1184 (1987).

59.

Donehower

Grochow

Longnecker

Ettinger

: Phase I trial of taxol in patients with advanced cancer. Cancer Treat. Rep. 71(12), 1171–1177 (1987).

60.

Brown

Havlin

Weiss

: A Phase I trial of taxol given by a 6-hour intravenous infusion. J. Clin. Oncol. 9(7), 1261–1267 (1991).

61.

Rowinsky

Burke

Karp

: Phase I and pharmacodynamic study of taxol in refractory acute leukemias. Cancer Res. 49(16), 4640–4647 (1989).

62.

Sarosy

Kohn

Stone

: Phase I study of taxol and granulocyte colony-stimulating factor in patients with refractory ovarian cancer. J. Clin. Oncol. 10(7), 1165–1170 (1992).

63.

Hurwitz

Relling

Weitman

: Phase I trial of paclitaxel in children with refractory solid tumors: a Pediatric Oncology Group Study. J. Clin. Oncol. 11(12), 2324–2329 (1993).

64.

Spriggs

Tondini

: Taxol administered as a 120 h infusion. Invest. New Drugs 10(4), 275–278 (1992).

Paclitaxel in Breast Cancer

Abstract

Keywords

Taxanes in breast cancer

Introduction to the compound

Chemistry

Mechanisms of action & resistance

Pharmacokinetics & metabolism

Clinical efficacy

Phase I studies

Phase II studies

Phase III studies in metastatic breast cancer

Phase III adjuvant studies

Safety & tolerability

Hypersensitivity reactions

Neutropenia

Neurotoxicity

Cardiotoxicity

Others

Regulatory affairs

Conclusion

Future perspective

References