The taxanes may be the most important addition to the cancer chemotherapeutic armamentarium. Due to its substantial antitumor activity, the clinical development of docetaxel(Drug information on 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.
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(Drug information on doxorubicin) (48% vs 33%, P = .008) in patients who had failed prior therapy with an alkylating agent. 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(Drug information on 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. 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(Drug information on 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.
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). 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). In a large phase III trial in patients pretreated with an anthracycline, the combination of docetaxel and capecitabine(Drug information on 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.
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(Drug information on gemcitabine) (Gemzar), vinorelbine, and trastuzumab(Drug information on 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.
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.
Additional randomized studies have evaluated docetaxel in combination with the anthracyclines, doxorubicin, and epirubicin(Drug information on epirubicin). The preliminary results achieved in the docetaxel-containing arm demonstrate improvement over those reported for the non-taxane-containing regimen. Docetaxel has also been successfully combined with cisplatin(Drug information on cisplatin) in the neoadjuvant setting, with high clinical and pathologic response rates, and a tolerable side-effect profile. 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.
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(Drug information on ifosfamide) (Ifex) in one trial, and compared to best supportive care in a second trial.
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(Drug information on 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.
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. 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. 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(Drug information on irinotecan) (CPT-11, Camptosar).[25,26] Further assessment of these combinations is necessary to determine their role in the first-line management of NSCLC.