ONCOLOGY Vol 14 No 8

HER2 is a member of the type I tyrosine kinase growth factor receptor family and participates in normal growth control mechanisms. It is overexpressed or amplified in 20% to 30% of breast cancers, as well as other carcinomas. HER2 overexpression is associated with adverse prognostic indicators in primary breast cancer, and a number of reports have shown that HER2-overexpressing breast cancer is linked to an increased rate of recurrence/metastases, and therefore, decreased disease-free and overall survival rates.

Ever since the first phase II study of paclitaxel (Taxol) began, there has been ongoing controversy about the optimal dose and schedule of administration of this drug. The initial reports of marked antitumor activity against metastatic breast cancer were obtained using 250 mg/m² administered by 24-hour continuous IV infusion. This schedule was originally developed in an attempt to reduce the incidence and severity of anaphylactic reactions. Subsequent to the determination that this dose and schedule was effective and safe, there were multiple attempts to develop more convenient schedules, and dose/schedules associated with an improved side-effect profile.

Currently there are a number of available agents that are moderately active in non–small-cell lung cancer (NSCLC). These include cisplatin (Platinol), gemcitabine (Gemzar), vinorelbine (Navelbine), paclitaxel (Taxol), docetaxel (Taxotere), and irinotecan (Camptosar). How best to combine them, maximizing survival while minimizing toxicity, is the subject of intense investigation.

The Southwest Oncology Cooperative Group (SWOG) conducted a study in which single-agent docetaxel (Taxotere) was used as “consolidation” therapy following concurrent chemoradiotherapy (abstract #1916). A previous SWOG study (S90-19) (Proc Am Soc Clin Oncol 16: 446a [abstract 1600], 1997) established that chemotherapy with cisplatin (Platinol)/etoposide could be given concurrently with definitive thoracic irradiation both safely and effectively. In this earlier trial, following the completion of irradiation, two additional cycles of cisplatin/etoposide were given.

Gómez-Bernal et al (abstract #341) report the results of a docetaxel (Taxotere)/vinorelbine (Navelbine) combination as second-line therapy for metastatic breast cancer. Both agents were administered on the same day and repeated every 14 days. The 52% objective response rate is impressive, since vinorelbine alone would be expected to produce a 20%–30% response rate in this setting, with docetaxel projected to achieve a 40% complete and partial remission rate. Therefore, the results suggest an additive interaction between the two agents.

Over the past 5 years it has become evident that the administration of taxanes on a weekly schedule dramatically changes their toxicity profile, compared to the standard 3-weekly schedule. Weekly docetaxel (Taxotere) is markedly less

Evidence generated by controlled clinical trials over the past 4 decades indicated that combination chemotherapy produced superior results to single-agent cytotoxic therapy. Response rates and times to progression were superior with combination chemotherapy, and survival was also favorably altered by this approach. This paradigm has been recently challenged on the basis of the Norton-Simon hypothesis and by the development of more effective, new cytotoxic agents, specifically the taxanes.

Abstracts #317 and #322 attest to the high degree of antitumor activity of docetaxel (Taxotere) in the management of locally advanced breast cancer. In abstract #317 the authors tested two hypotheses: first, that the administration of a non–cross-resistant cytotoxic regimen after induction or neoadjuvant chemotherapy improved the outcome of combined-modality treatment for both responders and nonresponders to neoadjuvant chemotherapy; and second, that the addition of docetaxel to a standard, anthracycline-containing regimen improved both clinical and pathologic response rates in locally advanced breast cancer.

Before the introduction of the taxanes into the management of breast cancer, the anthracyclines (and doxorubicin and epirubicin [Ellence] in particular) were considered the most active agents against this malignancy. The marked activity of single-agent taxanes suggested that their antitumor efficacy might match and perhaps exceed that of the anthracyclines. Several prospective randomized trials have confirmed these initial impressions. At intermediate doses (60 mg/m²), the activity of doxorubicin and paclitaxel (Taxol) was similar; at higher doses (75 mg/m²), doxorubicin appeared more effective. Conversely, docetaxel (Taxotere) was reported to be more active than doxorubicin in one trial.

Gemcitabine (Gemzar) has emerged from its initial clinical evaluation in patients with metastatic breast cancer as an effective antitumor agent. Its usual schedule of administration is weekly, and it is a very well-tolerated regimen. In combination with anthracyclines, the activity matches that of other commonly used multidrug regimens, including CMF (cyclophosphamide [Cytoxan, Neosar]/methotrexate/fluorouracil) or FAC (fluorouracil/doxorubicin [Adriamycin]/cyclophosphamide). When the taxanes became the most effective agents against breast cancer, two-drug and three-drug combinations with gemcitabine were initiated. This development was stimulated by the need to discover effective, non–cross-resistant regimens for patients previously exposed to anthracyclines and classical alkylating agents.

In abstract #403 the combination of docetaxel (Taxotere) and doxorubicin was tested in a prospective, multicenter, phase II trial, by one of the foremost breast cancer research cooperative groups-the National Surgical Adjuvant Breast and Bowel

In medically suitable patients with stage III (locally advanced) non–small-cell lung cancer, the use of cisplatin (Platinol)-based chemotherapy as induction therapy prior to definitive local therapy has been shown to improve survival (J Natl Cancer Inst 86:673-680, 1994; Ann Intern Med 125:723-729, 1996). This is true regardless of whether the local treatment modality used is surgery or thoracic irradiation. However, because cisplatin therapy is particularly toxic, there is interest in studying other agents in the induction setting. Given its activity in non–small-cell lung cancer, docetaxel (Taxotere) is one logical agent to investigate.

A meta-analysis of randomized controlled trials (Br Med J 311:899-909, 1995) has shown that the use of cisplatin (Platinol)-based combination chemotherapy in patients with good performance status leads to a modest improvement in median survival and an absolute increase in 1-year survival proportion of 10%. There are several different platinum-based regimens approved by the Food and Drug Administration for use in advanced non–small-cell lung cancer. Whether any one regimen is superior is unclear. A recent randomized controlled trial found no difference in median survival and quality of life between carboplatin (Paraplatin)/paclitaxel (Taxol)-the most commonly used regimen in the United States-and cisplatin/vinorelbine (Navelbine)-a regimen more popular in Europe and Canada (Proc Am Soc Clin Oncol 18: 461a [abstract 1777], 1999). The newer agents gemcitabine (Gemzar) and docetaxel (Taxotere) are among the most active single agents in non–small-cell lung cancer, and use of either in combination with cisplatin has shown promise.

These abstracts examine the use of single-agent docetaxel (Taxotere), an antimicrotubule agent and one of the most active drugs against NSCLC currently available, in the first- and second-line settings.

One hundred centers from Europe, the Middle East, Asia, and South America participated in a non–small-cell lung cancer (NSCLC) study with broad inclusion criteria (first and second line) to establish the toxicity and efficacy profile of docetaxel (Taxotere) at 100 mg/m² in worldwide clinical practice.

Docetaxel (Taxotere) is an active single agent in the treatment of non–small-cell lung cancer. Weekly administration of docetaxel minimizes myelosuppression and is generally well tolerated. To further evaluate the efficacy and toxicity of this novel schedule, we performed a phase II trial in patients with advanced non–small-cell lung cancer who were either elderly (age > 65 years) or poor candidates for combination chemotherapy due to coexistent illness or poor performance status.

Doxorubicin and docetaxel (Taxotere) are two of the most effective drugs in metastatic breast cancer when used in monotherapy. The objective of this study was to investigate the toxicity and efficacy of the use of both drugs in full doses and sequentially in patients with metastatic breast cancer with no previous chemotherapy.

A phase I trial demonstrated that monthly docetaxel (Taxotere) and weekly gemcitabine (Gemzar) had both acceptable toxicity and encouraging antineoplastic activity in patients with previously treated advanced breast cancer. This phase II trial will determine the efficacy and toxicity of this regimen in advanced breast cancer patients who have measurable disease refractory to, or relapsed after, first-line or adjuvant chemotherapy.

Epirubicin (Ellence) is currently being studied in combination with the taxanes, such as docetaxel (Taxotere), in patients with advanced breast cancer. As a single agent, docetaxel has proven to be a very active drug in breast cancer, so the results of these combination trials are awaited with interest. Our experience has shown epirubicin/docetaxel to be a feasible and active combination in breast cancer.

The most efficacious primary chemotherapy regimens used to treat breast cancer contain anthracyclines. Unfortunately, a significant proportion of breast cancers fail to respond to such therapy. Therefore the aims of this study were (1) to determine the efficacy of primary docetaxel (Taxotere) in patients that initially fail to respond to anthracycline-based primary chemotherapy, and (2) to compare the efficacy of docetaxel with anthracycline-based primary chemotherapy in patients that are initially responsive to such therapy.

This study was conducted to determine whether docetaxel (Taxotere) prior to definitive local treatment improves overall survival when compared to local treatment without prior chemotherapy in patients with radically treatable stage IIIA N2 (T0–3), T3 (N0-1) or IIIB non–small-cell lung cancer. Local treatment was defined at baseline.

The degree of pathologic response of tumor to primary chemotherapy is of considerable prognostic importance in patients with breast cancer. The addition of docetaxel (Taxotere) to an anthracycline-based primary chemotherapy regimen has been shown to result in significantly improved pathologic breast cancer response. The identification of predictors of treatment response will permit cytotoxic regimens to be tailored to individual patient requirements and permit pathologic response rates to be improved.

The aim of this study was to assess the efficacy and toxicity of the combination of docetaxel (Taxotere) and vinorelbine (Navelbine), every 15 days, in anthracycline-pretreated metastatic breast cancer patients.

Between June 1996 and March 1998, 429 first-line metastatic breast cancer patients were randomized to receive AT (doxorubicin [Adriamycin] 50 mg/m² and docetaxel [Taxotere] 75 mg/m²) or AC (doxorubicin 60 mg/m² and cyclophosphamide [Cytoxan, Neosar] 600 mg/m²), day 1 every 3 weeks for a maximum of eight cycles.

The combination of docetaxel (Taxotere) and doxorubicin is highly effective in breast cancer, but it presents relatively high hematologic toxicity. Recent data have suggested advantages for the weekly administration of docetaxel regarding the safety

The objective of this study was to assess the response rate and the toxicity of the combination docetaxel (Taxotere)/vinorelbine (Navelbine) in patients with advanced breast cancer.

The purpose of this study was to define the antitumor activity of the PGT (cisplatin [Platinol]/gemcitabine [Gemzar]/paclitaxel [Taxol]) combination in chemonaive non–small-cell lung cancer patients.

Docetaxel (Taxotere) and vinorelbine (Navelbine) are active agents in the treatment of metastatic breast cancer. Preclinical data suggest that there may be synergism between vinca alkaloids and taxane compounds. The current study evaluates the combination of docetaxel and vinorelbine with concurrent granulocyte colony-stimulating factor (G-CSF, filgrastim [Neupogen]) in anthracycline-refractory breast cancer. The objectives of this study are to determine the response rate, time to progression, survival, and toxicities of this regimen.

The purpose of this trial was to evaluate the efficacy and safety of weekly gemcitabine (Gemzar) plus monthly docetaxel (Taxotere) (J Clin Oncol 16:3866-3873, 1998) as second-line treatment for non–small-cell lung cancer.

Weekly administration of taxanes as palliative treatment in metastatic breast cancer has been reported with significantly reduced hematologic toxicity and comparable efficacy to standard every-3-week protocols. This study update provides mature results with weekly docetaxel (Taxotere) in a larger patient population.