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The Current Status of Docetaxel in Solid Tumors

The Current Status of Docetaxel in Solid Tumors

ABSTRACT: In less than a decade, docetaxel (Taxotere) has progressed from initial studies in anthracycline-refractory metastatic breast cancer to several large, phase III randomized trials evaluating its efficacy as adjuvant, neoadjuvant, and first-line therapy for metastatic breast cancer, non-small-cell lung cancer (NSCLC), and ovarian cancer. In other tumor types, including prostate, head and neck, gastric, and bladder cancer, ongoing phase III trials are comparing docetaxel-containing regimens to previously established regimens. For the seven tumor types reviewed in this supplement, phase III study information for docetaxel or docetaxel-based combinations are presented. Impressive results have been consistently demonstrated in the trials reported to date. In early-stage and metastatic breast cancer, NSCLC, and ovarian cancer, randomized trials have shown that docetaxel-containing therapies are superior to or as effective as established standard chemotherapeutic regimens and are often associated with an improved safety profile. Trials of docetaxel as adjuvant and neoadjuvant therapy for breast cancer are under way or have been completed. Docetaxel has demonstrated a survival benefit in many settings that previously had not achieved such a benefit. For example, a survival benefit was demonstrated in anthracycline-resistant breast cancer and second-line NSCLC cancer phase III comparative trials. [ONCOLOGY 16(Suppl 6):9-16, 2002]

The taxanes may be the most important addition to the cancer chemotherapeutic
armamentarium.[1] Due to its substantial antitumor activity, the clinical
development of docetaxel (Taxotere) has moved rapidly from the salvage
metastatic breast cancer setting to front-line investigation in several solid
tumor types, for which randomized phase III trials have been completed or are
under way. In addition, docetaxel is being evaluated in numerous adjuvant and
neoadjuvant clinical trials where its use in early-stage disease is likely to
have the greatest impact on patient outcome.

Breast Cancer

Docetaxel became commercially available in 1995 due to its efficacy in
anthracycline-resistant metastatic breast cancer as demonstrated in two phase II
clinical trials, one of which was performed by Dr. Vicente Valero and colleagues
at The University of Texas M. D. Anderson Cancer Center (MDACC).[2,3] Impressive overall response rates
of 53% and 57% were achieved in this setting.[2,3] An expanded indication for
single-agent docetaxel in the treatment of patients with locally advanced or
metastatic breast cancer after failure of prior chemotherapy was granted based
on the results of two large, phase III comparative trials. One study
demonstrated a significantly higher objective response rate for docetaxel vs
doxorubicin (48% vs 33%, P = .008) in patients who had failed prior therapy with
an alkylating agent.[4] This landmark trial was the first and only comparative
trial in which another single agent was shown to be more active than

A second phase III trial of single-agent docetaxel vs the combination of
mitomycin C (Mutamycin) and vinblastine in patients who had failed prior
anthracycline therapy demonstrated a survival benefit (11.4 months vs 8.7
months, P = .01) as well as higher objective response rates (30% vs 11.6%,
< .0001) for docetaxel.[7] Based on this trial, docetaxel is currently the
only agent to show a survival benefit in anthracycline-resistant metastatic
breast cancer. Two additional phase III trials in this patient population
demonstrated improved response rates and time to progression with single-agent
docetaxel vs combination chemotherapy with the fluorouracil (5-FU)/methotrexate
and 5-FU/vinorelbine (Navelbine) regimens.[8,9]

Docetaxel Combinations for Metastatic Breast Cancer

As reviewed by Dr. Francisco Esteva in this supplement, docetaxel continues
to be investigated in various combinations and schedules for the management of
metastatic breast cancer. An overall benefit to therapy was reported in a large
phase III trial in metastatic breast cancer for the combination of docetaxel (Taxotere)
and doxorubicin (Adriamycin) (AT) compared to a previously established standard
regimen of doxorubicin and cyclophosphamide (Cytoxan, Neosar) (AC). The AT
combination achieved a higher overall response rate (60% vs 47%, P = .012) with
improved time to progression (37.1 weeks vs 31.9 weeks, P = .015) compared to
the AC combination.[10]

Another phase III trial demonstrated improvement in overall response rates
(55% vs 42%) for the docetaxel-based TAC regimen
(docetaxel/doxorubicin/cyclophosphamide) vs the FAC regimen
(5-FU/doxorubicin/cyclophosphamide).[11] A randomized phase II trial
demonstrated that the docetaxel/epirubicin (Ellence) (ET) combination appears to
be superior to 5-FU/epirubicin/cyclophosphamide (FEC) in terms of overall
response rate (63% vs 34.3%) and time to progression (7.8 vs. 5.9 months).[12]
In a large phase III trial in patients pretreated with an anthracycline, the
combination of docetaxel and capecitabine (Xeloda) resulted in improved time to
progression (6.1 vs 4.2 months, P = .0001) and overall survival (14.1 vs 11.1
months, P = .0112) over docetaxel alone.[13]

Weekly dosing of docetaxel has been shown to maintain a high level of
efficacy with the advantage of a lower rate of myelosuppressive side effects.
The weekly administration schedule has opened additional avenues for combined
regimens with drugs that are routinely administered on a weekly basis, such as
gemcitabine (Gemzar), vinorelbine, and trastuzumab (Herceptin). From MDACC, Dr.
Esteva has recently reported the results of a trial combining weekly docetaxel
plus trastuzumab in metastatic breast cancer patients whose tumors overexpress
the HER2/neu oncoprotein.[14]

Adjuvant Therapy With Docetaxel

As discussed by Dr. Gabriel Hortobagyi, evidence of docetaxel’s high level
of activity in metastatic disease led to its swift entry into clinical trials in
the adjuvant setting. In this setting, in the treatment of early-stage breast
cancer patients, docetaxel is anticipated to have an even greater impact on
patient outcome and overall survival. Worldwide, most of the ongoing clinical
trials of adjuvant chemotherapy include a taxane-related question. The
docetaxel-containing regimens currently being investigated follow one of three
important strategies: (1) sequential therapy, with administration of docetaxel
added to existing, commonly used combinations; (2) combination therapy, with the
addition of docetaxel to an existing regimen; and (3) combination therapy, with
the substitution of docetaxel for one of the drugs included in standard

These three approaches are currently under investigation in many large,
multicenter, phase III prospective randomized clinical trials being conducted
around the globe. It is believed that the results of these trials will establish
the use of docetaxel in the curative treatment of breast cancer and will
determine the optimal method for the incorporation of docetaxel into standard
adjuvant therapy.

Docetaxel as Neoadjuvant Therapy

Another role for docetaxel currently under investigation is in the
preoperative, neoadjuvant setting, as discussed by Dr. Vicente
. To date,
the results of two phase III randomized studies of single-agent docetaxel
administered following an anthracycline-based regimen have demonstrated
improvement in terms of complete clinical and pathologic response rates, with
nearly a doubling of these two end points in the docetaxel arm.[15,16] In one
study for which long-term results are available, these findings translated into
significantly improved 3-year disease-free and overall survival rates.[15]

Additional randomized studies have evaluated docetaxel in combination with
the anthracyclines, doxorubicin, and epirubicin. The preliminary results
achieved in the docetaxel-containing arm demonstrate improvement over those
reported for the non-taxane-containing regimen.[17] Docetaxel has also been
successfully combined with cisplatin in the neoadjuvant setting, with high
clinical and pathologic response rates, and a tolerable side-effect profile.[18]
A trial of docetaxel combined with cisplatin and trastuzumab in patients with
HER2/neu-positive tumors demonstrated a high rate of pathologic complete
responses and axillary node clearance at the time of surgery.[19]

Non-Small-Cell Lung Cancer

The clinical development of docetaxel as therapy for non-small-cell lung
cancer (NSCLC) parallels its development in breast cancer, with initial trials
conducted in the second-line metastatic setting, followed quickly by its
introduction into the front-line setting.

As discussed in the article by Dr. Frank Fossella, docetaxel is the only
FDA-approved agent for use in locally advanced or metastatic NSCLC patients
after failure of prior platinum-based chemotherapy. This indication was approved
after a randomized phase III trial demonstrated a survival benefit in patients
treated with docetaxel who had failed prior platinum-containing chemotherapy.
Two large, randomized phase III trials were conducted in this setting, with
participation by MDACC as the lead institution for one of the studies.[20,21]
Results showed significantly improved response rates, time to progression,
survival, and quality of life for docetaxel compared to vinorelbine or
ifosfamide (Ifex) in one trial,[20] and compared to best supportive care in a
second trial.[21]

Dr. Fadlo Khuri reviewed the results of clinical trials of
docetaxel-containing combinations in the first-line NSCLC setting. Docetaxel has
been successfully combined with both cisplatin and carboplatin (Paraplatin). A
large, comparative four-arm trial conducted by the Eastern Cooperative Oncology
Group (ECOG) established docetaxel/cisplatin as a reasonable option for
first-line treatment of NSCLC.[22]

Phase III data establishing the combination of docetaxel and carboplatin as a
safe and active regimen for first-line treatment of NSCLC were recently
reported, with investigators at MDACC again serving as the lead institution.
This randomized phase III trial compared docetaxel/cisplatin or
docetaxel/carboplatin to vinorelbine/cisplatin.[23] Patients in the
docetaxel/cisplatin arm achieved superior overall and 2-year survivals. The
docetaxel/platinum regimens demonstrated safety and quality-of-life benefits
over vinorelbine/cisplatin.

Docetaxel has also been successfully combined with gemcitabine in multiple
trials in NSCLC patients with impressive response and survival rates and an
acceptable toxicity profile. Therapeutic equivalence and fewer toxicities were
noted for the docetaxel/gemcitabine combination compared to the
docetaxel/cisplatin combination in a large comparative trial.[24] The
docetaxel/gemcitabine combination therefore holds promise as a viable non-platinum-containing
regimen for first-line treatment of NSCLC. Other combinations that have been
investigated in NSCLC include docetaxel with vinorelbine and docetaxel with
irinotecan (CPT-11, Camptosar).[25,26] Further assessment of these combinations
is necessary to determine their role in the first-line management of NSCLC.


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