Docetaxel (Taxotere) is a semisynthetic taxane that promotes tubulin
assembly into microtubules, stabilizing microtubules and inhibiting depolymerization
to free tubulin, thereby blocking cells in the M phase of the cell cycle.[1,2]
In preclinical studies, the broad spectrum of in vitro and in vivo antitumor
activity of docetaxel has translated into clinical efficacy in a variety
of cancers, including breast, lung, ovarian, and others. The primary
toxicity of docetaxel is neutropenia, which generally resolves within 1
week. The incidence of thrombocytopenia and anemia associated with docetaxel
is low, occurring in less than 8% of patients.
Following hepatic transformation to active alkylating metabolites, cyclophosphamide
(Cytoxan, Neosar) produces predominately interstrand DNA cross-links, an
effect that is thought to be cell-cycle nonspecific. The combination
of docetaxel and cyclophosphamide is attractive for a number of reasons.
Both agents have been highly active in a wide range of solid tumors. In
addition, preclinical data demonstrate that docetaxel and cyclophosphamide
have synergistic effects against MA 13/C mammary adenocarcinoma.[6,7] In
preclinical combination studies, 60% to 70% of the maximum tolerated dose
of each agent could be administered safely.[6,7] Thus, the use of granulocyte
colony-stimulating factor (G-CSF) (filgrastim [Neupogen]) support may be
useful in ameliorating neutropenic events or enabling dose-escalation before
dose-limiting toxicities occur.
Determining the Maximum Tolerated Dose
Our group performed a phase I trial of docetaxel and cyclophosphamide
in 45 patients with advanced solid tumors to determine the maximum tolerated
dose in patients who had prior therapy for metastatic disease, and in patients
with untreated metastatic disease (with and without G-CSF support), as
well as to characterize the toxicity of this combination regimen.
The working definition of maximum tolerated dose in this trial was 1
dose level below the dose that produces a dose-limiting toxicity in 3 or
more patients during the first cycle. A dose-limiting toxicity was categorized
as grade 4 or greater nonhematologic toxicity, except nausea/vomiting;
grade 4 neutropenia of at least 8 days' duration; grade 4 neutropenia plus
fever, with or without infection; or grade 4 thrombocytopenia.
Eligibility criteria for study participation included patients with
a life expectancy of at least 3 months and with a Karnofsky performance
status of at least 60%. Patients were to have histologically confirmed
solid malignancies with bidimensionally measurable or evaluable disease.
Moreover, patients were to have adequate hematopoietic, renal, and hepatic
function. In addition, patients were to have no prior chemotherapy or radiation
therapy within 4 weeks of the study.
The treatment plan consisted of patients receiving cyclophosphamide
immediately followed by docetaxel, both administered over 1-hour as an
intravenous infusion, once every 3 weeks. The dose levels of cyclophosphamide/docetaxel
were 600/60 mg/m² (group 0), 600/75 mg/m² (group 1), 700/75 mg/m²
(group 2), 800/75 mg/m² (group 3), 800/85 mg/m² (group 4), 800/75
mg/m² (group 5), and 800/85 mg/m² (group 6).
Patients with dose-limiting neutropenia in groups 5 and 6 received 300
µg of G-CSF support on days 2 through 9 during subsequent cycles
of chemotherapy. All patients received premedication with 8 mg of dexamethasone
twice daily for 5 days beginning 1 day prior to chemotherapy.
Included in the analysis were 45 patients with a median age of 53 years
(range: 29 to 73 years) and a median Karnofsky performance status of 90%
(range: 60% to 90%). The tumor types among the 45 patients included metastatic
breast cancer (32 patients), sarcoma (6 patients), colon (3 patients),
and others, including lung and head/neck cancers (4 patients). The median
number of sites involved was 3 (range: 1 to 4).
The preliminary response rate for all tumor types was 51%, consisting
of 3 complete and 20 partial responses (Table
1). A total of 9 patients had stable disease, and the other 13 patients
experienced progression. When the data were analyzed for the 32 patients
with metastatic breast cancer, an objective response rate of 69% was noted,
with 3 patients achieving a complete response and 19 achieving partial
The combination of docetaxel and cyclophosphamide produced complicated
neutropenia in approximately 51% of the patients and 16% of the cycles.
Febrile neutropenia occurred in 20% of patients and 6% of cycles administered.
Similarly, grade 3 to 4 infections plus neutropenia were noted in 31% of
patients and only 8% of cycles.
In general, nonhematologic toxicities were mild in severity. Mucositis
was the most common gastrointestinal toxicity, occurring in 38% of patients
and 14% of cycles administered. Other common gastrointestinal toxicities
of grade 2 severity or higher were nausea in 27% and diarrhea in 20% of
the patients, respectively.
Subacute nonhematologic toxicities included moderate-to-severe fatigue
(75% of patients), myalgia (47%), mild peripheral neuropathy (22%), and
skin abnormalities (20%). Moderate-to-severe fluid retention occurred in
only 15% of patients, with no cases of significant pleural effusions.
The preliminary results from this phase I study are encouraging. The
combination of docetaxel and cyclophosphamide is potentially beneficial
for the palliation and adjuvant management of many neoplasias, including
breast cancer, non-small-cell lung cancer, non-Hodgkin's lymphoma, ovarian
cancer, and others. The initial objective response rate seen in patients
with metastatic breast cancer was 69%, with 3 patients achieving a complete
response. In addition, the combination of docetaxel and cyclophosphamide
in this phase I trial was well tolerated with no unexpected toxicities.
The dose-limiting toxicity was neutropenic fever. The addition of G-CSF
did not allow for additional dose escalation.
Based on these results, the recommended dose for phase II studies without
G-CSF support) is 700 mg/m² of cyclophosphamide followed by 75 mg/m²
of docetaxel, both given as 1-hour intravenous infusions, once every 3
weeks, for previously treated patients. For previously untreated patients,
cyclophosphamide can be given at a dose of 800 mg/m² followed by 75
mg/m² of docetaxel.
1. Gueritte-Voegelein F, Guenard D, Lavelle F, et al: Relationships
between the structure of Taxol analogues and their antimitotic activity.
J Med Chem 34:992-998, 1991.
2. Ringel I, Horwitz SB: Studies with RP 56976 (Taxotere): A semisynthetic
analogue of taxol. J Natl Cancer Inst 83:288-291, 1991.
3. Kaye SB: Docetaxel (Taxotere) in the treatment of solid tumors other
than breast and lung cancer. Semin Oncol 22(suppl 4):30-33, 1995.
4. Cortes JE, Pazdur R: Docetaxel. J Clin Oncol 13:2643-2655, 1995.
5. Hengstler JG, Hengst A, Fuchs J, et al: Induction of DNA crosslinks
and DNA strand lesions by cyclophosphamide after activation by cytochrome
P450 2B1. Mutat Res 373:215-223, 1997.
6. Bissery MC, Vrignaud P, Bayssas M, et al: Taxotere synergistic combination
with cyclophosphamide, etoposide, and 5-fluorouracil in mouse tumor models
(abstract). Proc Am Assoc Cancer Res 34:1782, 1993.
7. Bissery MC, Vrignaud P, Lavelle F: Preclinical profile of docetaxel
(Taxotere): Efficacy as a single agent and in combination. Semin Oncol
22(suppl 13):3-16, 1995.
8. Valero V, Esparza-Guerra L, Rahman Z, et al: Phase I study of docetaxel
(Taxotere) and cyclophosphamide without and with G- CSF in previously treated
and untreated solid neoplasms (abstract 772). Proc Am Soc Clin Oncol 16,