New Cytotoxic Agents for the Treatment of Breast Cancer

Introduction

Over the past 10 years, several new treatment strategies have been developed and many new agents have been evaluated for the treatment of metastatic breast cancer [1]. Some of these agents represent analogs of previously existing drugs, whereas others belong to new molecular families. Some agents have novel mechanisms of action, different from those of drugs used in the past. Several agents have been approved by the regulatory agencies for the treatment of breast cancer; others are still completing clinical evaluation, and many more are in preclinical evaluation. In this article, I will review agents with demonstrated efficacy against breast cancer (Table 1).

Amonafide

Amonafide (benzisoquinolinedione, nafidimide) is a synthetic compound with potent antiviral and cytotoxic activity. It acts as a DNA-intercalating agent and is an inhibitor of topoisomerase II [2]. Phase I trials using 3 different schedules were conducted: daily ´ 5 every 3 weeks, bolus infusion every 3 to 4 weeks, and 24-hour continuous infusion every 4 weeks. The dose-limiting toxicity was reversible myelosuppression. Nonhematologic toxicity was mild, consisting mostly of nausea and vomiting, which was easily controlled with antiemetics. The daily ´ 5 schedule of administration was recommended for phase II trials. The recommended phase II dosage was 300 mg/m² daily for 5 consecutive days. The daily dose was administered over 1 hour. Amonafide has modest antitumor activity against prostate and small-cell lung cancer. Three phase II trials performed in patients with breast cancer have been reported [3-5]. The overall activity of the drug was modest, between 15% and 20%. Two complete remissions were observed among 103 patients. The response rate was modest, even in patients who had undergone no prior chemotherapy.

Amonafide is acetylated to N-acetyl- amonafide [6,7]. Because of the known, marked individual variation in plasma concentration of N-acetyl-amonafide, an acetylator phenotype was determined in a small group of patients. Fast acetylators were found to have a much higher overall response rate (3 of 8; 38%) than slow acetylators (1 of 16; 6%).5 An acetylator phenotype also correlated with toxicity, suggesting that the recommended phase II dose was too high for fast acetylators and too low for slow acetylators (Table 2). Additional trials are indicated for this agent to confirm this latter observation, which suggests that in a subgroup of patients with breast cancer, amonafide has marked antitumor activity. Dosing based on an acetylator phenotype is being tested prospectively to improve the therapeutic ratio of this agent. Because extramedullary toxicity is modest, additional dose-escalation studies, perhaps with hematopoietic growth factor support, would be indicated to assess the full range of doses with this agent.

New Anthracyclines

Anthracyclines are the most active single agents in the treatment of breast cancer, but their clinical usefulness is limited by cardiotoxicity related tocumulativedos[8].Epirubicin is a potentially less cardiotoxic doxorubicin(Drug information on doxorubicin) analog, but it has not been approved by the Food and Drug Administration (FDA) because of insufficient supportive evidence. Several new anthracycline derivatives have entered clinical trials, and a few of them have been evaluated against metastatic breast cancer [8].

Theprubicin underwent phase II evaluation in the 1980s; several trials suggested activity equivalent to that of doxorubicin [9,10]. Limited phase II trials of theprubicin in combination therapy suggested no difference in activity between theprubicin- and doxorubicin-containing combinations [11]. However, no direct comparative trials have been reported.

Liposomal Doxorubicin (TLC D-99)--A new approach to reduce the toxicity of anticancer drugs is to encapsulate otherwise soluble drugs into multilamellar lipid particles (liposomes). Doxorubicin is the single most studied anticancer drug encapsulated in liposomes. TLC D-99 was developed with the intent of reducing the cardiotoxicity of doxorubicin. Phase I trials determined that an intermittent 3-weekly schedule was appropriate, and the maximum tolerated dose was found to be between 60 and 90 mg/m². Activity was similar to that of other anthracyclines in limited phase II studies [12]. In combination with standard agents, liposomal doxorubicin achieved efficacy similar to that of standard anthracycline-containing regimens [13]. To date, results suggest that higher cumulative doses can be administered with a lower incidence of and less severe cardiotoxicity than those of the soluble free agent. However, comparative trials to determine the relative efficacy and safety of this agent are just completing accrual. Other liposome-encapsulated anthracyclines are entering phase I/II studies, but the results of such studies have not yet been published.

Anthrapyrazoles

The anthracenediones (mitoxantrone [Novantrone], bisantrene, and others) were developed to reduce the frequency and severity of anthracycline-induced cardiotoxicity [14]. Although mitoxantrone(Drug information on mitoxantrone) is less cardiotoxic than the anthracyclines, it is also somewhat less effective. For this reason, mitoxantrone has not received FDA approval for treatment of breast cancer. The anthrapyrazoles are structurally similar to mitoxantrone [15]. They maintain the planar conformation and cationic nature of the anthracyclines, essential for DNA intercalation. Several anthrapyrazoles have been developed.

Losoxantrone (CI-941)--Preclinical evaluation demonstrated that losoxantrone induced both single- and double-stranded breaks in DNA and was a potent inhibitor of DNA synthesis [16]. In preclinical models, it was less cardiotoxic than doxorubicin [17]. Phase I clinical trials demonstrated that when losoxantrone was administered in an intermittent single-dose schedule, the maximum tolerated dose was 55 mg/m², and the dose-limiting toxicities were leukopenia and neutropenia [18].

At least two phase II studies of losoxantrone have been reported [19,20]; both included previously untreated and previously treated patients with metastatic breast cancer. The objective response rates obtained in these studies are shown in Table 3. A few complete remissions were observed, and response durations in these trials compared favorably with those expected after standard combination chemotherapy. Toxicity consisted mostly of leukopenia, although up to 40% of patients were reported to have alopecia. Acute toxicity was negligible. However, a recent update reported that 3% of patients developed congestive heart failure [21]. Therefore, this agent is as active as or more active than existing anthracyclines; however, the drug is not devoid of cardiotoxicity.

Teloxantrone (CI-937)--This second anthrapyrazole has also completed phase I/II clinical trials [22,23]. At least one phase II study in breast cancer has been reported in abstract form [23]. At an early stage of follow-up, there were major objective responses in 9 of 47 patients, and a minor response was achieved in another 11% (Table 3). No additional information is available about this trial. The pattern, frequency, and severity of toxicity appeared to be similar to those of losoxantrone.

Piroxantrone--Piroxantrone hydrochloride (oxantrazole, NSC-349174) is the third anthrapyrazole compound currently undergoing testing in clinical trials [24]. No reports of its activity in breast cancer are available at this time.

Camptothecin Analogs

Topoisomerases are recognized targets for anticancer agents. Topoisomerase I makes a single cut in the DNA duplex and relieves transcription-associated torsional strain. Camptothecin, a plant alkaloid with broad-spectrum activity and a novel mechanism of action, was isolated from Camptotheca acuminata more than 2 decades ago. In the early 1970s, phase I clinical trials showed marked hematologic and nonhematologic toxicity, including severe cystitis; this led to the conclusion that the compound was too toxic for clinical development. More recently, several novel semisynthetic and synthetic analogs designed to be less toxic and to overcome the problems associated with pharmaceutical formulations of natural products have appeared. These analogs are completing clinical development. The parent compound and the recently developed analogs inhibit both DNA and RNA synthesis by topoisomerase I-mediated effects [25]. The analogs of interest in the area of breast cancer research and treatment include topotecan(Drug information on topotecan), irinotecan(Drug information on irinotecan), and probably SN-38. The relative efficacy and toxicity of the camptothecin analogs were evaluated in preclinical models [26].

Topotecan--Topotecan is a potent, water-soluble camptothecin analog with a broad spectrum of antitumor activity, including human colorectal, non-small- cell lung, ovarian, breast, and renal cell carcinomas [25].

In phase II trials, topotecan was administered at a dosage of 1.5 mg/m² daily for 5 consecutive days to patients with metastatic breast cancer who had received minimal or no prior chemotherapy treatment. Cycles of treatment were repeated every 3 weeks [27]. Sixteen patients had been treated at the time of the report, 14 of whom were evaluable. Five patients achieved a partial response (36%), and 1 patient achieved a minor response. Three patients had stable disease, with the remaining five patients showing progression of metastatic disease. Myelosuppression, especially granulocytopenia, was observed. Mild fatigue, mild to moderate alopecia, and skin rashes were also reported.

Irinotecan (CPT-11) is another water-soluble camptothecin analog. Although it also is a topoisomerase I inhibitor, unlike camptothecin and topotecan, CPT-11 has limited antitumor activity in vitro. In vivo, it is converted to 7-ethyl-10-hydroxy-camptothecin (SN-38), a metabolite with a 100-fold greater antitumor activity than CPT-11 in vitro. This agent has antitumor activity against small-cell and non-small-cell lung cancer, gynecologic and gastrointestinal tumors, and leukemia and lymphoma. Until recently, severe side effects, such as leukopenia and diarrhea, had limited its clinical development.

In a recently reported phase II trial, irinotecan was administered to patients with metastatic breast cancer who had undergone minimal or no prior chemotherapy [28]. The agent was administered intravenously over 30 minutes at a dosage of 350 mg/m² every 3 weeks. Of 29 patients treated, 21 were evaluable at the time of the report; these patients had a good performance status and a moderate amount of tumor burden. Twelve patients were evaluable for response. One achieved a complete remission, whereas four others ex- perienced no change. The remaining seven patients had progressive disease. Grade II or higher nausea and vomiting, diarrhea, abdominal cramps, alopecia, neutropenia, asthenia, and hot flashes were reported. Three patients were removed from the study because of toxicity.

In a second study, reported in abstract form only, 15 (23%) of 65 patients responded to irinotecan treatment [29]. No information is available about the duration of treatment or the effect of camptothecin analogs on quality of life.