Preclinical data demonstrate in vitro synergy for combinations of docetaxel(Drug information on docetaxel) (Taxotere) and cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar). As single agents, both drugs have proven highly active against a wide range of human solid tumors, including breast cancer, non-small-cell carcinoma of the lung, bladder cancer, and other neoplasms.
Administration of docetaxel--a product of Taxus baccata, the European yew--at a dose of 75 mg/m² has resulted in objective response rates of 52% as first-line therapy in 31 evaluable patients with advanced breast cancer. In phase II studies of patients with previously untreated breast cancer receiving 100 mg/m²of docetaxel, an overall response rate of 61% was achieved in 137 evaluable patients.[4-7]
After the anthracyclines, the nitrogen mustard-alkylating agent cyclophosphamide is the second-most active agent in metastatic breast cancer. It is also a cornerstone in adjuvant and neoadjuvant therapies in early breast cancer. These observations led us to study the efficacy and safety of docetaxel/cyclophosphamide combination therapy.
The primary objectives of this phase I study were as follows:
- Determine the maximum tolerated doses (MTDs) of cyclophosphamide and docetaxel in patients with solid tumors
- Report the qualitative and quantitative toxicity of the two drugs in combination, administered intravenously over 1 hour every 21 days, as well as the reversibility of toxicity.
To be eligible, patients had to have a histologically confirmed advanced solid malignancy (any type) and measurable or evaluable disease. Other criteria included a life expectancy 3 months or more and Karnofsky performance status 60% or more, no prior chemotherapy or radiation within the previous 4 weeks, and normal or only mildly impaired liver function.
Dosage was escalated in seven levels, from 60 to 85 mg/m² docetaxel and from 600 to 800 mg/m²cyclophosphamide (Table 1). The two highest dosage levels (85 mg/m² of docetaxel plus 800 mg/m² of cyclophosphamide and 75 mg/m² of docetaxel plus 800 mg/m² of cyclophosphamide) were evaluated with and without granulocyte colony-stimulating factor (G-CSF, filgrastim(Drug information on filgrastim) [Neupogen]). On days 3 through 9, 300 mg of G-CSF was administered. All patients received steroid prophylaxis in the form of 8 mg of dexamethasone(Drug information on dexamethasone) twice daily, beginning the day before chemotherapy and continuing through day 4.
To date, 39 patients have been enrolled: 26 with breast cancer, 6 with sarcoma, 3 with colon cancer, and 4 with other solid tumors, including lung 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 4 neutropenia with fever, requiring intravenous antibiotics with or without hospitalization. In general, as shown in Table 1, 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 grade 2 or lower. As with other taxoids and other chemotherapeutic agents, fatigue and myalgia were common. Fatigue was moderate in many patients and severe in only a few. Arthralgia/joint pain occurred in some patients who received G-CSF.
Although neurotoxicity was generally a minor problem, one patient had grade 3 neurotoxicity. Seven patients (18%) had edema, but none developed clinically significant pleural effusion or required discontinuation of treatment due to fluid retention. Nonhematologic toxicities grade 2 or more are summarized in Table 2.
Two groups of patients were analyzed: those who had received prior chemotherapy and those who had not. This analysis suggested two recommended doses: 75 mg/m² of docetaxel combined with 700 mg/m² of cyclophosphamide in previously treated patients, and 75 mg/m² of docetaxel combined with 800 mg/m² of cyclophosphamide in previously untreated patients.
Neutropenic fever was the dose-limiting toxicity. Experience has shown that premedication with dexamethasone reduces toxicity due to fluid retention. In this study, all patients received steroid prophylaxis, and there was no clinically significant pleural effusion in any patient.
The addition of G-CSF did not permit further dose escalation, in that all three of the patients receiving the highest dose level developed neutropenic fever. However, G-CSF did shorten the duration of neutropenia from 7 to 9 days to 3 to 4 days. The ability of G-CSF to permit dosage escalation may depend on the setting. Most of the patients in this study had previously treated metastatic disease and some degree of organ dysfunction. Higher doses facilitated by growth factor may be more feasible in the adjuvant setting, in previously untreated or minimally treated patients. This merits further investigation.
In summary, preliminary results show that the combination of docetaxel and cyclophosphamide is well tolerated with no unexpected toxicity in breast cancer patients, many of whom had been previously treated.