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Paclitaxel

An Update of its Use in the Treatment of Metastatic Breast Cancer and Ovarian and Other Gynaecological Cancers

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Abstract

Synopsis

The antitumour agent paclitaxel has proved to be effective for the treatment of patients with metastatic breast or ovarian cancer, and limited data also indicate its clinical potential in patients with cervical or endometrial cancer. The regimen of paclitaxel administration has varied in clinical trials, the most common including a dosage of between 135 and 250 mg/m2 administered over an infusion period of 3 or 24 hours once every 3 weeks. Promising results have been achieved in phase I/II trials of a weekly regimen of paclitaxel (60 to 175 mg/m2).

The objective response rate in patients with metastatic breast cancer (either pretreated or chemotherapy- naive) is generally between 20 and 35% with paclitaxel monotherapy, which compares well with that of other current treatment options including the anthracycline doxorubicin. Combination therapy with paclitaxel plus doxorubicin appears superior to treatment with either agent alone in terms of objective response rate and median duration of response. However, whether combination therapy also provides a survival advantage remains unclear; recent results of a phase III study indicate that it does not. Paclitaxel is also a useful second- line option in some patients with anthracycline- resistant disease.

Combination therapy with paclitaxel and cisplatin has proved highly effective as first- line therapy for patients with advanced ovarian cancer, showing superior efficacy to cyclophosphamide/cisplatin in terms of progression- free survival time and median duration of survival. Combination therapy with paclitaxel and carboplatin has also shown promising results. Paclitaxel monotherapy is a useful second- line option for patients with platinum- refractory metastatic ovarian cancer (objective response rates have ranged from 15 to 48%).

The major dose-limiting adverse events associated with paclitaxel include myelotoxicity and peripheral neuropathy. Paclitaxel has acceptable tolerability in most patients, although adverse events are common.

Conclusion. Paclitaxel generally appears to be as effective as other antineoplastic agents used in the treatment of metastatic breast cancer, including doxorubicin. Importantly, it is a useful second- line option for some patients with anthracycline- resistant disease. Combination therapy with both paclitaxel and doxorubicin is a highly effective first- line option for metastatic breast cancer; however, recent results indicate no survival advantage versus monotherapy. Paclitaxel is a valuable agent for second- line treatment of patients with platinum- refractory metastatic ovarian cancer and, when combined with cisplatin or carboplatin, is recommended as first- line therapy for this disease.

Overview of Pharmacodynamic Properties

The ability of paclitaxel to bind to microtubules and inhibit the normal dynamic reorganisation of the microtubule network is thought to play an important role in inhibition of cell replication. Apoptosis has also been observed in cells exposed to paclitaxel.

Paclitaxel inhibits the growth of a wide variety of tumour cells including those of ovarian, breast, cervical and endometrial origin. This activity may be synergistically enhanced in vitro when paclitaxel is combined with other antineoplastic agents including cisplatin, doxorubicin and fluorouracil. However, the order in which cells are exposed to these agents appears to be an important determinant of synergism or antagonism. In addition, paclitaxel can enhance the sensitivity of many cell types to the effects of irradiation.

Paclitaxel-resistant tumours may have increased expression of the multidrug-resistance mdr-1 gene, alterations in α- or β-tubulin or altered expression of specific β-tubulin genes.

Other effects of paclitaxel include concentration-dependent suppression of human peripheral blood mononuclear and natural killer cell cytotoxicity against cancer cell lines, inhibition of microtubule-associated functions of neutrophils, and enhancement of stimulated release of the proinflammatory cytokines interleukin-1β and tumour necrosis factor-α. Paclitaxel has been associated with reversible neurological toxicity, most frequently resulting in numbness or paraesthesia, in some patients.

Overview of Pharmacokinetic Properties

Plasma concentrations of paclitaxel increase throughout intravenous infusion and decline thereafter. Plasma concentrations achieved at steady state with doses ≥ 135 mg/m2 are higher than concentrations shown in vitro to produce antimicrotubule effects.

The drug’s pharmacokinetic behaviour appears to be nonlinear after administration of doses of 135 or 175 mg/m2 by 3- or 24-hour infusion.

Initial plasma clearance is rapid, but it is followed by a more prolonged elimination period. Paclitaxel is 88 to 98% plasma protein bound and has a large volume of distribution.

The predominant route of elimination of paclitaxel is by hepatic metabolism and biliary clearance. The main metabolite is 6α-hydroxypaclitaxel.

Administration of paclitaxel prior to doxorubicin causes a significant increase in peak plasma concentrations (Cmax) of the anthracycline and prolongation of both the distribution and elimination half-life of the latter drug. Cmax and the area under the plasma concentration-time curve for the anthracycline metabolite doxorubicinol were also significantly increased. No pharmacokinetic interaction was observed with the reverse schedule.

Clearance of paclitaxel may be reduced by prior administration of cisplatin, whereas carboplatin has no apparent effect. Fluconazole and ketoconazole inhibited the metabolism of paclitaxel in vitro.

Clinical Efficacy

Paclitaxel has proved to be an effective agent for the treatment of patients with metastatic breast or ovarian cancer and, although data are limited, also appears to have potential in patients with endometrial or cervical cancer. The most frequently used regimen in clinical trials has been a 3- or 24-hour infusion given once every 3 weeks. Dosages have ranged between 135 and 250 mg/m2. A weekly schedule of paclitaxel (60 to 175 mg/m2) has also shown promising results in recent phase I/II trials. Neutropenia is the most common dose-limiting toxicity.

Breast Cancer. In patients with advanced breast cancer, clinical response rates to paclitaxel monotherapy have ranged between 17 and 86%; most falling within the 20 to 35% range. The drug has shown efficacy in both chemotherapy-naive and previously treated patients (including some patients with anthracycline-resistant disease). The median duration of response is generally between 4 and 8 months and median survival between 9.5 and 22.2 months. Treatment efficacy appears to be dose related.

Comparisons with other antineoplastic regimens are limited; however, paclitaxel monotherapy appears to be at least as effective as standard CMFP (cyclophosphamide, methotrexate, fluorouracil, prednisone) combination therapy (although overall survival tended to be longer with paclitaxel) and superior to mitomycin monotherapy. Recent results from phase III studies have shown variable results regarding the relative efficacy of paclitaxel versus doxorubicin. In one study, both drugs showed similar efficacy in terms of objective response rates, median time to treatment failure and median duration of survival, whereas in another, improvements in both the objective response rate and median progression-free survival were significantly in favour of doxorubicin.

Clinical response rates and the median duration of response are generally higher when patients are given combination therapy with paclitaxel and other antineoplastic agents than with paclitaxel alone. First-line combination therapy with paclitaxel and doxorubicin produced objective response rates ranging from 69 to 94% in phase I/II studies, with complete responses in 8 to 41% of patients. The median duration of objective response was between 8 and 11 months and median time to disease progression was between 9 and 12 months. Results from a phase III study indicate that combination therapy with doxorubicin/paclitaxel is more effective than monotherapy with either agent in terms of clinical response rate and median time to treatment failure; however, no survival advantage was observed (median duration of survival 19 to 22 months for all treatment groups).

Objective response rates appear similar to those achieved with paclitaxel/doxorubicin when paclitaxel is combined with either epirubicin or cisplatin (although they are more variable). Combination therapy with cyclophosphamide and various high-dose regimens have also shown promising results.

Ovarian Cancer. Paclitaxel monotherapy produced objective responses in 15 to 48% of patients with platinum-refractory advanced ovarian cancer in clinical trials with ≥44 participants. The median duration of response ranged from 4.9 to 9.2 months, median duration of progression-free survival from 14 weeks to 12 months and overall survival time from 8.1 to 15.6 months. As with breast cancer, response rates tended to be dose related.

Combination therapy with paclitaxel and cisplatin or carboplatin achieved response rates generally between 70 and 79% when used to treat patients with no prior chemotherapy experience.

When used as first-line treatment in patients with metastatic ovarian cancer, combination therapy with paclitaxel and cisplatin has proved to be superior to cyclophosphamide/cisplatin in terms of survival benefit. In a phase III study, the median progression-free survival time was 18 versus 13 months and median duration of survival was 38 versus 24 months (p < 0.001). The objective response rate was 73 versus 60% (p = 0.01).

Pharmacoeconomic analyses tended to favour combination therapy with cisplatin and paclitaxel with regard to long term survival benefit. Although first-line treatment costs were higher with this regimen than with cisplatin/cyclophosphamide, when the survival benefit was incorporated into the analyses, there was a moderate increase in incremental costs for cisplatin/paclitaxel which compared well with that of other life-prolonging therapies.

Tolerability

The most common adverse events in patients treated with paclitaxel include neutropenia, anaemia, peripheral neuropathy, myalgia/arthralgia, mucositis and alopecia. Treatment discontinuation because of severe events is rarely necessary [16 of 458 patients (4%) withdrew in one study].

Myelotoxicity is often dose limiting, but neutropenia usually resolves within 3 to 10 days. Furthermore, myelotoxicity may be reduced by administration of granulocyte colony-stimulating factor. The incidence of myelotoxicity appears higher with a 24- versus a 3-hour infusion, and with a dose of 175 mg/m2 versus 135 mg/m2. Whereas paclitaxel showed similar haematological tolerability to standard CMFP therapy, its tolerability relative to that of doxorubicin was unclear. However, paclitaxel 200 mg/m2 was far better tolerated than doxorubicin 75 mg/m2 in a phase III study (grade 4 neutropenia 40 vs 85% and neutropenic fever 7 vs 20%). Haematological toxicity may be greater with paclitaxel/carboplatin combination therapy than with paclitaxel/cisplatin; however, this requires confirmation. The tolerability of paclitaxel/cisplatin relative to cisplatin/cyclophosphamide has yet to be clarified.

The administration schedule used may affect the tolerability of combination therapy. Haematological toxicity was greater when paclitaxel preceded doxorubicin (although this may not be the case with a shorter infusion time) or cyclophosphamide or when cisplatin preceded paclitaxel compared with the respective reverse schedules.

Peripheral neuropathy is a common nonhaematological toxicity which can be dose limiting in paclitaxel recipients. Its severity and incidence appear to be dose and schedule related, cumulative and occur earlier in the course of therapy when higher doses are administered. Patients with pre-existing neuropathy or other risk factors for neuropathy tend to be at greater risk. The incidence of peripheral neuropathy may be increased (compared with paclitaxel monotherapy) when paclitaxel is administered after, or in combination with, cisplatin. Myalgia or arthralgia also develop 2 to 3 days after paclitaxel administration in some patients (59% of 458 patients in one study) and appear to be dose related. However, most events are mild to moderate.

Cardiovascular events occur in a small number of patients treated with paclitaxel. However, the majority of events, including transient asymptomatic bradycardia and hypotension, are rarely considered to be clinically relevant. It remains unclear whether the incidence of cardiac toxicity is increased (versus doxorubicin) when paclitaxel is combined with doxorubicin. Although some phase II studies have shown a significant reduction in left ventricular ejection fraction in patients treated with the combination, and the development of congestive heart failure in some patients, results from a phase III study indicate that the incidence of cardiac toxicity is similar in patients treated with doxorubicin alone or in combination with paclitaxel. Paclitaxel plus epirubicin appears well tolerated with respect to possible cardiac events, although data are limited.

Other adverse events include alopecia (in most patients), mucositis and nausea and vomiting (common but rarely severe), and, less frequently, taste impairment, diarrhoea, anorexia, sore throat, stomatitis, fatigue, fever, oedema, hypotension, hypomagnesaemia, dyspnoea, headache, facial flushing, phlebitis, transient hepatocellular dysfunction and hypersensitivity reactions.

Dosage and Administration

Paclitaxel 135 or 175 mg/m2 administered intravenously over a 3-hour infusion period once every 3 weeks is recommended for the treatment of patients with ovarian cancer, and 175 mg/m2 by 3-hour intravenous infusion once every 3 weeks is recommended for patients with breast cancer. Subsequent courses of paclitaxel should be administered only when neutrophil and platelet counts have recovered to an adequate level, and the dosage should be reduced by 20% if patients develop severe neutropenia or severe peripheral neuropathy. The drug may be given either as first-line therapy or to patients who have received prior chemotherapy.

First-line combination therapy with paclitaxel preceded by doxorubicin appears to be more effective than paclitaxel monotherapy in patients with advanced breast cancer, and first-line combination therapy with cisplatin or carboplatin after paclitaxel appears more effective than paclitaxel monotherapy in patients with metastatic ovarian cancer.

Premedication with oral dexamethasone, intravenous diphenhydramine (or clemastine) and cimetidine or ranitidine is recommended to reduce the risk of hypersensitivity reactions to paclitaxel. Continuous cardiac monitoring is not necessary during paclitaxel therapy, except in patients with serious pre-existing conduction abnormalities.

Although few data are available concerning the use of paclitaxel in patients with liver impairment, lower dosages of the drug should be administered to these patients.

As paclitaxel is poorly soluble in water, it is formulated in a vehicle of 50% polyoxyethylated castor oil and 50% alcohol (ethanol).

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Wiseman, L.R., Spencer, C.M. Paclitaxel. Drugs Aging 12, 305–334 (1998). https://doi.org/10.2165/00002512-199812040-00005

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