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 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
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 [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 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
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
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.
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