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The Current Status of Docetaxel in Solid Tumors
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The Current Status of Docetaxel in Solid Tumors
Review Article [1] | June 01, 2002 | Lung Cancer [2], Bladder Cancer [3], Ovarian Cancer [4]
By Waun Ki Hong, MD [5]
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.
he 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.
T
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 doxorubicin.[5,6]
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%, P < .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
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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 combinations.
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 Valero. 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]
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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.
Hormone-Refractory Prostate Cancer
Dr. Christopher Logothetis reviews the data showing that docetaxel-based chemotherapy regimens
are among the most effective treatment options for patients with advanced prostate cancer. As
reviewed in his article, compelling results achieved with docetaxel in phase I and II studies provided
the rationale for the large, phase III randomized trials in hormone-refractory prostate cancer.[27-30]
The cooperative research groups, Cancer and Leukemia Group B (CALGB), North Central Cancer
Treatment Group (NCCTG), and the Southwest Oncology Group (SWOG) are conducting an intergroup
comparative study (SWOG 9916) of an every-3-week schedule of docetaxel/estramustine (Emcyt) vs
mitoxantrone (Novantrone)/prednisone.[31] The primary end point of the study is survival.
A second, randomized phase III trial has three arms: the control arm of mitoxantrone plus prednisone
is being compared to an every-3-week schedule of docetaxel plus prednisone, or weekly docetaxel
plus prednisone.[32] Survival again is the primary end point in this trial. The results of these studies
will better define the role of docetaxel-based therapy in hormone-refractory prostate cancer.
Investigational studies of docetaxel in the treatment of earlier stages of prostate cancer are also
being pursued. Docetaxel is being evaluated in patients with rising prostate-specific antigen (PSA)
levels after definitive local therapy (ie, biochemical recurrence). Preliminary results of studies
incorporating docetaxel show promise in the setting of biochemical recurrence, where the optimal
treatment of prostate cancer patients has not yet been established.[33,34]
Two neoadjuvant studies of weekly single-agent docetaxel followed by radical prostatectomy in
high-risk prostate cancer patients have been reported.[35,36] Preliminary results demonstrated that
the weekly schedule of docetaxel was well tolerated, with the majority of treated patients showing
decreases in their serum PSA levels. Continued analysis of these and other neoadjuvant study results
for high-risk prostate cancer patients will determine the effect of docetaxel on the pathologic end
points.
Ovarian Cancer
Dr. John Kavanagh discusses how docetaxel has extended the armamentarium of active agents in
ovarian cancer. Data compiled from four phase II studies, one of which was conducted by Kavanagh
et al at MDACC in patients previously treated with a platinum agent, demonstrated a combined
overall response rate of 30% and a 6-month duration of response to docetaxel.[37] Yet another study
conducted at MDACC demonstrated the activity of docetaxel in patients with paclitaxel-resistant
disease.[38]
In the setting of first-line therapy for ovarian cancer, docetaxel has been successfully combined with
both cisplatin and carboplatin.[39,40] A large, phase III randomized trial (Scottish Randomized Trial
in Ovarian Cancer [SCOTROC]) that compared docetaxel/carboplatin to paclitaxel/carboplatin
resulted in equivalent overall response rates and progression-free survivals.[40] Hematologic
toxicities were more prominent with the docetaxel/carboplatin combination; however, they did not
result in treatment delays or early discontinuation of treatment.
In contrast, a higher rate of clinically significant neurotoxicity was reported with the
paclitaxel/carboplatin combination, and was associated with the need for significantly more dose
reductions and treatment discontinuations. In addition, neurotoxicity persisted longer in patients
after they went off study. Therefore, the docetaxel/carboplatin regimen may represent a viable
alternative to paclitaxel/carboplatin as first-line chemotherapy for advanced ovarian cancer.
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Squamous Cell Carcinoma of the Head and Neck
The current status of docetaxel in the management of squamous cell carcinoma of the head and
neck is reviewed by Dr. Bonnie Glisson. As a single agent, docetaxel has demonstrated an overall
response rate of 24% to 45% in patients with recurrent squamous cell carcinoma of the head and
neck.[41-44] These findings led to the investigation of docetaxel-based doublets and triplets in both
the recurrent and neoadjuvant setting. When combined with cisplatin (plus or minus 5-FU) in the
treatment of recurrent disease, response rates of 33% to 44% have been observed with median
survivals ranging from 9.6 to 11 months.[45-47]
Representing MDACC, Dr. Glisson participated in a phase I/II multi-institution trial that demonstrated
the feasibility and safety of the TPF regimen (docetaxel/cisplatin/5-FU) as induction therapy.[48] The
response and histologic complete response rates were equivalent to or better than those reported in
a randomized trial of cisplatin/5FU. Currently, the docetaxel/cisplatin combination is being compared
to cisplatin/5-FU in a randomized phase III trial in patients with recurrent or metastatic squamous cell
carcinoma of the head and neck.[49]
In the neoadjuvant setting, response rates with docetaxel-based regimens have typically been
greater than 90%, with promising disease-free and overall survival results.[50-53] Consequently,
randomized trials are currently under way to assess the value of docetaxel-based therapy relative to
that of the standard combinations used in the neoadjuvant treatment of squamous cell carcinoma of
the head and neck. The TPF regimen is being compared to the combination of cisplatin/5-FU (PF) in a
randomized, phase III trial in patients with locally advanced, curable squamous cell carcinoma of the
head and neck.[54] The results will determine if the TPF regimen offers a therapeutic advantage over
standard PF, and the trial provides a model for future comparisons of sequential chemotherapy with
chemoradiotherapy regimens.
Gastric Cancer
As discussed by Dr. Jaffer Ajani, docetaxel has been successfully used in the treatment of advanced
gastroesophageal tumors both as a single agent and in combination. Phase II results of single-agent
docetaxel demonstrate an overall response rate of 17% to 24%, with complete responses being
achieved in a tumor for which complete responses are rare.[55-58] As a result, docetaxel is
considered among the most active agents in gastrointestinal carcinoma. Other research initiatives in
gastric cancer have evaluated combinations of docetaxel with agents traditionally used for the
treatment of the disease, such as cisplatin and 5-FU. Results of phase II studies of docetaxel-based
combinations demonstrate response and progression-free survival rates comparable to those
achieved with established three- and four-drug regimens.[59,60]
From MDACC, Ajani et al reported the results of a phase II study in previously untreated patients
randomized to treatment with either TC (docetaxel/cisplatin), or TCF (docetaxel/cisplatin/5-FU).[61]
The three-drug regimen resulted in a slightly higher incidence of nonhematologic toxicities; however,
it also resulted in a higher overall response rate (52% vs 45%). The TCF regimen was, therefore,
chosen as the experimental arm of an ongoing phase III trial comparing it to the widely used control
arm of 5-FU/cisplatin.[62]
Another ongoing phase III trial is comparing the combination of docetaxel and cisplatin to
5-FU/cisplatin.[63] It is anticipated that the addition of the individually active docetaxel to
established standard agents will ultimately improve palliation and possibly the survival of patients
with gastroesophageal tumors.
Combined-Modality Therapy With Docetaxel and Radiation
Drs. Edward Kim and Fadlo Khuri summarize the results of studies investigating docetaxel as a
component of combined-modality therapy. Docetaxel has been studied in combination with radiation
for the treatment of NSCLC, head and neck cancer, and esophageal cancer.[64-66] Trials in patients
with NSCLC have evaluated the combination of docetaxel and platinum agents with radiation, and
early results show promising activity and acceptable toxicity.[67,68] Generally, esophagitis or
mucositis are the dose-limiting toxicities. Current trials are evaluating different design schedules,
including concurrent chemotherapy with radiation followed by consolidation docetaxel. Additional
trials of docetaxel-based chemoradiotherapy in the neoadjuvant and adjuvant settings in early
NSCLC are warranted.
Transitional Cell Carcinoma of the Urothelium
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Drs. Christopher Logothetis and Randall Millikan review the clinical data on docetaxel use in
transitional cell carcinoma of the urothelium. In advanced or metastatic transitional cell carcinoma of
the urothelium, docetaxel yielded promising results in previously treated and chemotherapy-naive
patients, as well as in patients with renal impairment who were unable to receive cisplatin-based
regimens.[69-71] Docetaxel has been combined with cisplatin for bladder cancer, resulting in
response rates of 52% to 60% and median overall survivals of 8 to 13.6 months.[72-74] Triple-drug
combinations based on the docetaxel/platinum regimen have been investigated, and the addition of
an anthracycline (doxorubicin or epirubicin) or of gemcitabine has proven feasible, with the result
being favorable efficacy findings.[75-77]
Non-platinum-containing regimens such as docetaxel/gemcitabine are being studied, and preliminary
results suggest that the combination is feasible and active.[78] Randomized phase III trials of a
docetaxel-containing regimen compared with the established MVAC regimen (methotrexate,
vinblastine, doxorubicin, cisplatin) are ongoing. Additional studies are warranted to determine if the
overall long-term survival of patients with transitional cell carcinoma of the urothelium can be
improved.
Conclusions
Docetaxel has been logically and progressively developed over the past decade in several tumor
types. Randomized phase III trial results have produced a wealth of information on its safety and
efficacy as both a single agent and in combination in the treatment of the many solid tumors
discussed here. Investigators at MDACC have had the foresight to investigate docetaxel in a variety
of oncologic settings, and have participated in many landmark trials that have brought docetaxel to
the forefront of the care of cancer patients. The recent availability of results from large, phase III
randomized trials in neoadjuvant breast cancer and front-line therapy of metastatic breast cancer,
NCSLC, and ovarian cancer demonstrate the superiority or at least equivalence of
docetaxel-containing regimens over previously established regimens for these tumor types. The
findings indicate that docetaxel-based regimens may represent the new standard of care based on
therapeutic index and patient benefits.
The results of ongoing phase III trials of docetaxel-based regimens for prostate, head and neck,
gastric and bladder cancer are eagerly awaited to further define their role in the therapy of these
diseases. Furthermore, the findings from ongoing trials of docetaxel in the adjuvant and neoadjuvant
settings are anticipated in regard to their potential impact on patient outcome, and ultimately,
survival in several tumor types. The next decade will likely be concerned with investigation of the
recently identified taxane mechanisms of action, as molecular biological capabilities and the
prognostic significance of molecular markers are refined. The development of additional taxane drug
combinations, schedules, and regimens with newly available therapies hold promise for the future in
the management of solid tumors.
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