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Paclitaxel and docetaxel each possess unique chemical and pharmacologic characteristics that account for significant differences in their potencies, toxicologic and pharmacokinetic profiles, and propensity for drug-drug interactions. Results from phase I/II trials of paclitaxel in combination with doxorubicin showed excellent antitumor activity. However, the high incidence of congestive heart failure warranted further investigation. A sophisticated pharmacokinetic study showed that paclitaxel enhances the nonlinearity of doxorubicin pharmacokinetics and significantly decreases the systemic clearance of both doxorubicin and doxorubicinol. The paclitaxel/doxorubicin interaction was found to be paclitaxel-dose dependent, doxorubicin concentration-dependant, and may be the result of competition for elimination mechanisms, possibly competition for hepatic and biliary transporter proteins such as p-glycoprotein, as a result of the formulation vehicle polyethoxylated castor oil (cremophor EL). Phase I/II trials of the docetaxel/doxorubicin combination also show high antitumor activity, but without an increase in anthracycline-induced congestive heart failure. Subsequent pharmacokinetic investigations show minimal alterations in the pharmacokinetic profiles of doxorubicin or docetaxel when used in combination. While both paclitaxel and docetaxel may be effectively combined with doxorubicin in the treatment of metastatic breast cancer, the drug-drug interaction between paclitaxel and doxorubicin (but not of docetaxel and doxorubicin) warrants that certain restrictions be followed for safe use., (Copyright 2001 by W.B. Saunders Company.)

Since both doxorubicin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) have substantial antitumor activity in advanced breast cancer, the combination of these two agents was a logical extension of the clinical development of paclitaxel. Early attempts used long infusions of both drugs, limiting the dose of both agents because of limiting gastrointestinal and myelosuppressive toxicity. Bolus doxorubicin combined with 3-hour infusion paclitaxel was reported to have dramatic antitumor activity, but clinically relevant cardiac toxicity in up to 20% of patients in two recent reports. In our current study the same schedules and doses of administration were used, limiting the total doxorubicin dose of 360 mg/m2. In-depth monitoring of cardiac function with noninvasive tests and endomyocardial biopsy were performed. Preliminary results suggest that, at these doses and schedule, the two-drug combination is safe, without unexpected toxicity. Limiting doxorubicin dose to 360 mg/m2 limits cardiac toxicity to levels expected from single-agent doxorubicin at similar cumulative doses.

The development of anthracycline/paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combinations has gone through several phases or generations. The first dose escalation studies used prolonged infusions of doxorubicin (48 to 72 hours) and paclitaxel (24 hours). Myelosuppression, mucositis, and neutropenic fever were dose limiting, and a sequence-dependent interaction was noted. In a second phase, doxorubicin was administered by bolus, without changing the schedule of the taxane. More recently, bolus doxorubicin was combined with 3-hour paclitaxel infusions. Higher doses of both agents were administered in this latter schedule, with higher overall response rates reported. Excessive cardiac toxicity was reported with the initial trials that used this schedule. Confirmatory studies are under way pursuing several alternatives to reduce the risk of cardiac toxicity; these include limiting the cumulative dose of doxorubicin, inserting an interval between the administration of the two drugs, and adding a cardioprotective agent to the combination. The high degree of antitumor activity of this combination is quite encouraging, and additional evaluation of this regimen in controlled trials is warranted in metastatic and high-risk primary breast cancer.

The first phase II study of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in breast cancer was completed at M.D. Anderson Cancer Center, and included 25 patients with metastatic breast cancer who had been previously treated with one chemotherapy regimen. Fourteen of these patients achieved a major objective response; the median response duration was 9 months, and the median survival time, 20 months. Additional trials showed that paclitaxel maintained its antitumor efficacy in patients with two and three prior chemotherapy regimens, including patients with anthracycline-resistant breast cancer. Combination therapy with doxorubicin showed that this combination was effective, although with the long infusion duration used for both agents, sequence-dependent toxic interactions were encountered. In combination with vinorelbine, dose-limiting toxicity included neutropenic fever and neuropathy. High-dose single-agent paclitaxel is currently being explored in the management of inflammatory breast cancer and as part of neoadjuvant chemotherapy for stages II and III operable disease.

The taxanes and the anthracyclines are clearly the most effective agents available to treat breast cancer. Developing combinations based on these two drug types is a logical direction in clinical investigation. The doxorubicin/paclitaxel doublet has been evaluated by several groups using a variety of doses and schedules of administration. Preliminary data from single-arm phase I/II trials suggest that when administered as consecutive short infusions, these two drugs produce a high overall response rate with tolerable toxicity. Whether the complete remission rates, response durations, and survival rates achieved with this combination are equally promising awaits additional confirmatory trials, including ongoing randomized trials that compare this doublet with doxorubicin/cyclophosphamide. The apparent increase in the incidence of clinical congestive heart failure (approximately 20%) observed in the Milan and Copenhagen trials is a potential limitation of the long-term administration of this combination. Limiting the cumulative dose of doxorubicin, adding cardioprotectors, and substituting less cardiotoxic anthracylines (ie, epirubicin) represent investigational efforts to minimize cardiac toxicity.

After the single-agent activity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) was confirmed, trials to develop a synergistic combination began. Doxorubicin, the most active agent for breast cancer, was studied first. As paclitaxel became more available, other combinations, including high-dose regimens and adjuvant therapies, have been studied. No optimal combination regimen has been defined. Recent and/or ongoing trials are looking at paclitaxel in combination with cisplatin, cyclophosphamide, 5-fluorouracil/ folinic acid, and mitoxantrone combinations, as well as with high-dose regimens and as adjuvant therapy. This review describes a plethora of combination studies finally under way to better define the optimal use of paclitaxel in breast cancer therapies, both as adjuvant treatment and for metastatic disease. Because of the unpredictable nature of drug interactions related to schedule and sequence, ad hoc combinations should not be undertaken outside the context of a well-designed trial.

Combinations of active antineoplastic agents have been the most effective treatment for metastatic breast cancer. Criteria for an effective combination include use of drugs with different mechanisms of action, nonoverlapping toxic effects, and synergistic, or at least additive, antitumor activity. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), with its unique mechanism of action, offers an excellent opportunity for development of effective combination therapy against breast cancer. However, a number of problems have hindered the rapid development of effective combinations. The most obvious problem is the lack of a defined optimal dose and schedule of administration. The second problem has been the demonstration of unexpected interactions between paclitaxel and the other component(s) of the combination, often resulting in unusual and serious toxic effects. This review will focus on the phase I and II trials of paclitaxel in combination with established antineoplastic drugs (except doxorubicin and congeners, which is covered elsewhere in this issue) for breast cancer: cisplatin, 5-fluorouracil with or without folinic acid, cyclophosphamide, radiation therapy, as well as novel investigational agents or strategies, edatrexate, monoclonal antibodies to oncogenes, growth factors, and gene therapy with insertion of multidrug resistance gene into blood stem cells. Combination therapy offers exciting possibilities of enhanced antitumor efficacy. However, given the unexpected and serious toxic effects observed, only proven combinations should be used outside the context of a clinical trial. Additionally, the burden of proof will be to show that these combinations have increased antitumor activity, decreased toxicity, or both compared with single-agent paclitaxel.

Initial trials using a 24-hour intravenous infusion of 250 mg/m2 paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of breast cancer yielded objective regression in 56% to 62% of patients with no or only one prior chemotherapy regimen. Tolerance to single-agent paclitaxel seemed acceptable, but after multiple cycles, peripheral neuropathy developed in a significant fraction of patients. Lower doses and, more recently, the 3-hour infusion schedule still produced objective responses, albeit lower, in the range of 20% to 35%. It became apparent that toxicity was dose and schedule dependent, and likely there was a dose-response correlation. A 96-hour infusion schedule yielded a maximum tolerated dose of 140 mg/m2, and no hypersensitivity reactions despite omission of the standard triple-drug premedication. More recently, a 1-hour infusion schedule (plus standard triple-drug premedication) was well tolerated, with activity in both lung and breast cancer similar to that observed after a 3-hour infusion treatment. Paclitaxel retained therapeutic activity, even among patients with anthracycline-refractory breast cancer, in clinical trials using the 3-, 24-, and 96-hour infusion of paclitaxel. Current ongoing trials will explore the range of paclitaxel activity of various doses and by alternative schedules, both as second-line therapy and in the adjuvant and neoadjuvant setting.

The first of three trials at M.D. Anderson Cancer Center investigating paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in metastatic breast cancer was a phase II study involving 25 patients (297 courses) previously treated with only one chemotherapy regimen; the patients received paclitaxel 250 mg/m2 infused over 24 hours without granulocyte colony-stimulating factor (G-CSF). Complete (12%) and partial responses (44%) led to median durations of response and survival of 9 and 21 months, respectively. The median paclitaxel dose was 200 mg/m2. Despite profound neutropenia (median granulocyte count of 0.3 cells x 10(9)/L for the first three courses), infection occurred in 42% of patients but only 6% of courses. In a phase I trial of paclitaxel 125 mg/m2 over 24 hours followed by doxorubicin 60 mg/m2 using G-CSF at 5 micrograms/kg days 5 through 19, dose-limiting mucositis with neutropenic fever occurred at the starting dose, so the maximum tolerated dose was one dose lower: paclitaxel 125 mg/m2 (over 24 hours) followed by doxorubicin 48 mg/m2 over 48 hours. Among 10 patients, there was one complete response and seven partial responses (overall response, 80%). Suspecting a schedule-dependent interaction between drugs, a phase I trial of the reverse sequence yielded a maximum tolerated dose, defined by neutropenic fever without mucositis, of doxorubicin 60 mg/m2 (over 48 hours) followed by paclitaxel 150 mg/m2 (over 24 hours) in 21 patients. A pharmacokinetic study in which the sequence of administration of paclitaxel over 24 hours and doxorubicin over 48 hours was alternated in courses 1 and 2 indicated that when paclitaxel by 24-hour infusion is given first, doxorubicin plasma levels at the end of infusion were an average 70% higher and doxorubicin clearance was reduced approximately 30% compared with the reverse sequence. Similarly, the incidence of grade 2 or 3 mucositis was 70% with the paclitaxel/doxorubicin sequence versus only 10% with the reverse sequence. We concluded that paclitaxel slows doxorubicin metabolism and that when used together in this schedule, doxorubicin should precede paclitaxel. In the third trial paclitaxel without G-CSF was administered to two groups of heavily pretreated patients: (1) those with only two prior chemotherapy regimens (inclusive of adjuvant therapy) received paclitaxel 175 mg/m2 over 24 hours and (2) those with three or more prior regimens received paclitaxel 150 mg/m2 over 24 hours. Response rates in both regimens were approximately 20%. We conclude that paclitaxel has significant antitumor activity in metastatic breast cancer, especially in patients with limited prior therapy, without need for G-CSF.(ABSTRACT TRUNCATED AT 400 WORDS)

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) 250 mg/m2 by 24-hour infusion at 21-day intervals was evaluated at M.D. Anderson Cancer Center as a single agent in patients who had received one prior chemotherapy regimen either as adjuvant therapy or for metastatic disease. Of 25 patients treated, 12% had a complete remission and 44% had a partial response. The median time to progression was 9 months (range, 1 to 20 months). In the next phase of development, a phase I trial evaluated sequentially administered paclitaxel and doxorubicin as initial therapy for metastatic disease. Granulocyte colony-stimulating factor also was administered in each cycle. The dose-limiting toxicity was either stomatitis or neutropenic fever. The maximum tolerated dose (MTD) was 125 mg/m2 for paclitaxel and 48 mg/m2 for doxorubicin. Because of much lower than anticipated MTDs of both drugs in this schedule, it was hypothesized that there may be a schedule-dependent toxicity; therefore, in the second phase I study the schedule of administration was reversed (ie, doxorubicin followed by paclitaxel infusion). The MTDs of this schedule were 60 mg/m2 and 150 mg/m2 for doxorubicin and paclitaxel, respectively. Pharmacokinetic studies subsequently have confirmed that administration of paclitaxel before doxorubicin impairs the elimination of doxorubicin by some unknown mechanism. In an ongoing phase II study, paclitaxel is being evaluated in patients who have received three or more treatments with chemotherapy. Paclitaxel is administered at doses of 135 and 150 mg/m2 (for poor- and good-risk patients, respectively) without granulocyte colony-stimulating factor. Six patients (19%) have shown objective partial responses. Our initial phase II study showed significant antitumor activity for paclitaxel in patients who had received limited prior chemotherapy. Our phase I studies established that initial administration of paclitaxel alters the pharmacokinetics of doxorubicin and increases morbidity. The reverse sequence of administration was associated with better tolerance and a higher MTD. In heavily treated patients this drug also has significant antitumor activity.

Fifty-five patients with newly diagnosed, estrogen receptor negative, metastatic breast cancer were entered in a trial of mitoxantrone, 10 mg/m2 intravenous (IV), cyclophosphamide, 500 mg/m2 IV, and 5-fluorouracil, 1000 mg/m2 IV, which were given on day 1 of a 21-day treatment interval. This trial was designed to test the efficacy of substituting mitoxantrone for doxorubicin as part of a combination that has proved to be effective in inducing remission. The trial was also intended to evaluate the response of resistant disease and of stable metastatic disease to a combination of doxorubicin and vinblastine sulfate. The cardiotoxic potential of mitoxantrone was evaluated in all the patients by serial measurements of ejection fraction and by endocardial biopsy of the right ventricle. Patients who achieved a complete response or a partial response (with bone as the only site of disease) on the three-drug combination were continued on this treatment for 2 years, or for 1 year following a complete response, whichever was shorter or as cardiac monitoring permitted. Therapy with doxorubicin, 25 mg/m2/d for two days, followed by continuous infusion vinblastine sulfate, 1.4 mg/m2/d for four days, was given to all patients who progressed after two courses or were stable after six courses of three-drug therapy. The preliminary results from 50 patients show that 4 attained a complete response and 30 a partial response, giving a total response rate of 68%. The median duration of response was more than 7 months (range greater than 5 to greater than 15 months). One patient in complete remission relapsed after 8 months and failed reinduction therapy with doxorubicin-vinblastine sulfate. Myelosuppression, principally granulocytopenia, was the major side effect of cyclophosphamide-mitoxantrone-5-fluorouracil. Mild to moderate vomiting occurred in 76% of patients and alopecia in 88%. This therapy was discontinued in four patients because of a decreased cardiac ejection fraction and/or symptoms of heart failure. No cardiac biopsy score, however, has been greater than 1.0. These results suggest that a combination of cyclophosphamide-mitoxantrone-5-fluorouracil is effective in untreated, estrogen receptor negative, metastatic breast cancer and is comparable to the doxorubicin combination. Myocardial injury occurs with mitoxantrone, and a safe cumulative dose has yet to be established.