This trial was designed to determine the recommended maximum tolerated dose (MTD), toxicity, pharmacokinetics, and efficacy of docetaxel (Taxotere) and cyclophosphamide (Cytoxan, Neosar) for phase II studies. Both drugs were administered to 39 patients with advanced solid tumors, 26 of whom had breast cancer.
ABSTRACT: This trial was designed to determine the recommended maximum tolerated dose (MTD), toxicity, pharmacokinetics, and efficacy of docetaxel (Taxotere) and cyclophosphamide (Cytoxan, Neosar) for phase II studies. Both drugs were administered to 39 patients with advanced solid tumors, 26 of whom had breast cancer. Docetaxel doses ranged from 60 to 85 mg/mÂ² and cyclophosphamide doses ranged from 600 to 800 mg/mÂ². All patients received steroid prophylaxis. The MTDs for patients with a history of prior chemotherapy were 75 mg/mÂ² of docetaxel and 700 mg/mÂ² of cyclophosphamide. For patients with no prior chemotherapy, the MTDs were 75 mg/mÂ² of docetaxel and 800 mg/mÂ² of cyclophosphamide. The dose-limiting toxicity was neutropenic fever, observed in 41% of patients and 13% of cycles. Addition of granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]) did not permit further dose escalation, although it did result in briefer periods of neutropenia. [ONCOLOGY 11(Suppl 6):21-23, 1997]
Preclinical data demonstrate in vitro synergy for combinations of docetaxel(Taxotere) and cyclophosphamide (Cytoxan, Neosar). As single agents,both drugs have proven highly active against a wide range of human solidtumors, including breast cancer, non-small-cell carcinoma of the lung,bladder cancer, and other neoplasms.
Administration of docetaxel--a product of Taxus baccata, theEuropean yew--at a dose of 75 mg/m² has resulted in objective responserates of 52% as first-line therapy in 31 evaluable patients with advancedbreast cancer. In phase II studies of patients with previously untreatedbreast cancer receiving 100 mg/m²of docetaxel, an overall responserate of 61% was achieved in 137 evaluable patients.[4-7]
After the anthracyclines, the nitrogen mustard-alkylating agent cyclophosphamideis the second-most active agent in metastatic breast cancer. It is alsoa cornerstone in adjuvant and neoadjuvant therapies in early breast cancer.These observations led us to study the efficacy and safety of docetaxel/cyclophosphamidecombination therapy.
The primary objectives of this phase I study were as follows:
To be eligible, patients had to have a histologically confirmed advancedsolid malignancy (any type) and measurable or evaluable disease. Othercriteria included a life expectancy 3 months or more and Karnofsky performancestatus 60% or more, no prior chemotherapy or radiation within the previous4 weeks, and normal or only mildly impaired liver function.
Dosage was escalated in seven levels, from 60 to 85 mg/m² docetaxeland from 600 to 800 mg/m²cyclophosphamide (Table1). The two highest dosage levels (85 mg/m² of docetaxel plus800 mg/m² of cyclophosphamide and 75 mg/m² of docetaxel plus800 mg/m² of cyclophosphamide) were evaluated with and without granulocytecolony-stimulating factor (G-CSF, filgrastim [Neupogen]). On days 3 through9, 300 mg of G-CSF was administered. All patients received steroid prophylaxisin the form of 8 mg of dexamethasone twice daily, beginning the day beforechemotherapy and continuing through day 4.
To date, 39 patients have been enrolled: 26 with breast cancer, 6 withsarcoma, 3 with colon cancer, and 4 with other solid tumors, includinglung and head and neck carcinomas. Of these 39 patients, 38 are evaluable.Most of these patients had been heavily pretreated.
The major toxicity was febrile neutropenia, defined as grade 3 or 4neutropenia with fever, requiring intravenous antibiotics with or withouthospitalization. In general, as shown in Table1, doses of the combination above the lowest level were highly myelosuppressive.Febrile neutropenia with or without infection was observed in 16 (41%)of the 38 patients and 25 (13%) of the 175 cycles.
The nonhematologic acute adverse events were minor; most were grade2 or lower. As with other taxoids and other chemotherapeutic agents, fatigueand myalgia were common. Fatigue was moderate in many patients and severein only a few. Arthralgia/joint pain occurred in some patients who receivedG-CSF.
Although neurotoxicity was generally a minor problem, one patient hadgrade 3 neurotoxicity. Seven patients (18%) had edema, but none developedclinically significant pleural effusion or required discontinuation oftreatment due to fluid retention. Nonhematologic toxicities grade 2 ormore are summarized in Table 2.
Two groups of patients were analyzed: those who had received prior chemotherapyand those who had not. This analysis suggested two recommended doses: 75mg/m² of docetaxel combined with 700 mg/m² of cyclophosphamidein previously treated patients, and 75 mg/m² of docetaxel combinedwith 800 mg/m² of cyclophosphamide in previously untreated patients.
Neutropenic fever was the dose-limiting toxicity. Experience has shownthat premedication with dexamethasone reduces toxicity due to fluid retention.In this study, all patients received steroid prophylaxis, and there wasno clinically significant pleural effusion in any patient.
The addition of G-CSF did not permit further dose escalation, in thatall three of the patients receiving the highest dose level developed neutropenicfever. However, G-CSF did shorten the duration of neutropenia from 7 to9 days to 3 to 4 days. The ability of G-CSF to permit dosage escalationmay depend on the setting. Most of the patients in this study had previouslytreated metastatic disease and some degree of organ dysfunction. Higherdoses facilitated by growth factor may be more feasible in the adjuvantsetting, in previously untreated or minimally treated patients. This meritsfurther investigation.
In summary, preliminary results show that the combination of docetaxeland cyclophosphamide is well tolerated with no unexpected toxicity in breastcancer patients, many of whom had been previously treated.
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