New Cytotoxic Agents for the Treatment of Breast Cancer

ABSTRACT: Over the past 5 years, many new cytotoxicagents with activity against metastatic cancer have been discovered,and several are currently undergoing clinical trials. Whethertheir marked degree of activity represents a real difference comparedwith that of drugs developed in the past 2 decades or simply reflectschanges in methodology is difficult to ascertain, as is the mostappropriate setting in which to employ these agents in the managementof breast cancer. It is unlikely that any of these agents alonewill change the natural history of metastatic breast cancer. Inthe future, such options as adding these single agents to existingcombinations, substituting these agents for other agents in existingcombinations, or developing entirely new combinations with emergingnew agents need to be explored. These new combinations must thenbe compared with existing and commonly used combinations to determinewhich option should be used as the treatment of choice for untreatedpatients with metastatic breast cancer. [ONCLOGY 10(Suppl):21-29,1996]

Introduction

Over the past 10 years, several new treatment strategies havebeen developed and many new agents have been evaluated for thetreatment of metastatic breast cancer [1]. Some of these agentsrepresent analogs of previously existing drugs, whereas othersbelong to new molecular families. Some agents have novel mechanismsof action, different from those of drugs used in the past. Severalagents have been approved by the regulatory agencies for the treatmentof 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 breastcancer (Table 1).

Amonafide

Amonafide (benzisoquinolinedione, nafidimide) is a synthetic compoundwith potent antiviral and cytotoxic activity. It acts as a DNA-intercalatingagent and is an inhibitor of topoisomerase II [2]. Phase I trialsusing 3 different schedules were conducted: daily ´ 5 every3 weeks, bolus infusion every 3 to 4 weeks, and 24-hour continuousinfusion every 4 weeks. The dose-limiting toxicity was reversiblemyelosuppression. Nonhematologic toxicity was mild, consistingmostly of nausea and vomiting, which was easily controlled withantiemetics. The daily ´ 5 schedule of administration wasrecommended for phase II trials. The recommended phase II dosagewas 300 mg/m² daily for 5 consecutive days. The daily dosewas administered over 1 hour. Amonafide has modest antitumor activityagainst prostate and small-cell lung cancer. Three phase II trialsperformed 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. Theresponse rate was modest, even in patients who had undergone noprior chemotherapy.

Amonafide is acetylated to N-acetyl- amonafide [6,7]. Becauseof the known, marked individual variation in plasma concentrationof N-acetyl-amonafide, an acetylator phenotype was determinedin a small group of patients. Fast acetylators were found to havea 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 forfast acetylators and too low for slow acetylators (Table 2). Additionaltrials 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 acetylatorphenotype is being tested prospectively to improve the therapeuticratio of this agent. Because extramedullary toxicity is modest,additional dose-escalation studies, perhaps with hematopoieticgrowth factor support, would be indicated to assess the full rangeof doses with this agent.

New Anthracyclines

Anthracyclines are the most active single agents in the treatmentof breast cancer, but their clinical usefulness is limited bycardiotoxicity related tocumulativedos[8].Epirubicin is a potentiallyless cardiotoxic doxorubicin analog, but it has not been approvedby the Food and Drug Administration (FDA) because of insufficientsupportive evidence. Several new anthracycline derivatives haveentered clinical trials, and a few of them have been evaluatedagainst 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 combinationtherapy suggested no difference in activity between theprubicin-and doxorubicin-containing combinations [11]. However, no directcomparative trials have been reported.

Liposomal Doxorubicin (TLC D-99)--A new approach to reducethe toxicity of anticancer drugs is to encapsulate otherwise solubledrugs into multilamellar lipid particles (liposomes). Doxorubicinis the single most studied anticancer drug encapsulated in liposomes.TLC D-99 was developed with the intent of reducing the cardiotoxicityof doxorubicin. Phase I trials determined that an intermittent3-weekly schedule was appropriate, and the maximum tolerated dosewas found to be between 60 and 90 mg/m². Activity was similarto that of other anthracyclines in limited phase II studies [12].In combination with standard agents, liposomal doxorubicin achievedefficacy similar to that of standard anthracycline-containingregimens [13]. To date, results suggest that higher cumulativedoses can be administered with a lower incidence of and less severecardiotoxicity than those of the soluble free agent. However,comparative trials to determine the relative efficacy and safetyof this agent are just completing accrual. Other liposome-encapsulatedanthracyclines are entering phase I/II studies, but the resultsof such studies have not yet been published.

Anthrapyrazoles

The anthracenediones (mitoxantrone [Novantrone], bisantrene, andothers) were developed to reduce the frequency and severity ofanthracycline-induced cardiotoxicity [14]. Although mitoxantroneis less cardiotoxic than the anthracyclines, it is also somewhatless effective. For this reason, mitoxantrone has not receivedFDA approval for treatment of breast cancer. The anthrapyrazolesare structurally similar to mitoxantrone [15]. They maintain theplanar conformation and cationic nature of the anthracyclines,essential for DNA intercalation. Several anthrapyrazoles havebeen developed.

Losoxantrone (CI-941)--Preclinical evaluation demonstratedthat losoxantrone induced both single- and double-stranded breaksin DNA and was a potent inhibitor of DNA synthesis [16]. In preclinicalmodels, it was less cardiotoxic than doxorubicin [17]. Phase Iclinical trials demonstrated that when losoxantrone was administeredin an intermittent single-dose schedule, the maximum tolerateddose was 55 mg/m², and the dose-limiting toxicities wereleukopenia and neutropenia [18].

At least two phase II studies of losoxantrone have been reported[19,20]; both included previously untreated and previously treatedpatients with metastatic breast cancer. The objective responserates obtained in these studies are shown in Table 3. A few completeremissions were observed, and response durations in these trialscompared favorably with those expected after standard combinationchemotherapy. Toxicity consisted mostly of leukopenia, althoughup to 40% of patients were reported to have alopecia. Acute toxicitywas negligible. However, a recent update reported that 3% of patientsdeveloped congestive heart failure [21]. Therefore, this agentis as active as or more active than existing anthracyclines; however,the drug is not devoid of cardiotoxicity.

Teloxantrone (CI-937)--This second anthrapyrazole has alsocompleted phase I/II clinical trials [22,23]. At least one phaseII study in breast cancer has been reported in abstract form [23].At an early stage of follow-up, there were major objective responsesin 9 of 47 patients, and a minor response was achieved in another11% (Table 3). No additional information is available about thistrial. The pattern, frequency, and severity of toxicity appearedto be similar to those of losoxantrone.

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

Camptothecin Analogs

Topoisomerases are recognized targets for anticancer agents. TopoisomeraseI makes a single cut in the DNA duplex and relieves transcription-associatedtorsional strain. Camptothecin, a plant alkaloid with broad-spectrumactivity and a novel mechanism of action, was isolated from Camptothecaacuminata more than 2 decades ago. In the early 1970s, phaseI clinical trials showed marked hematologic and nonhematologictoxicity, including severe cystitis; this led to the conclusionthat the compound was too toxic for clinical development. Morerecently, several novel semisynthetic and synthetic analogs designedto be less toxic and to overcome the problems associated withpharmaceutical formulations of natural products have appeared.These analogs are completing clinical development. The parentcompound and the recently developed analogs inhibit both DNA andRNA synthesis by topoisomerase I-mediated effects [25]. The analogsof interest in the area of breast cancer research and treatmentinclude topotecan, irinotecan, and probably SN-38. The relativeefficacy and toxicity of the camptothecin analogs were evaluatedin preclinical models [26].

Topotecan--Topotecan is a potent, water-soluble camptothecinanalog with a broad spectrum of antitumor activity, includinghuman colorectal, non-small- cell lung, ovarian, breast, and renalcell carcinomas [25].

In phase II trials, topotecan was administered at a dosage of1.5 mg/m² daily for 5 consecutive days to patients with metastaticbreast cancer who had received minimal or no prior chemotherapytreatment. Cycles of treatment were repeated every 3 weeks [27].Sixteen patients had been treated at the time of the report, 14of whom were evaluable. Five patients achieved a partial response(36%), and 1 patient achieved a minor response. Three patientshad stable disease, with the remaining five patients showing progressionof metastatic disease. Myelosuppression, especially granulocytopenia,was observed. Mild fatigue, mild to moderate alopecia, and skinrashes were also reported.

Irinotecan (CPT-11) is another water-soluble camptothecinanalog. Although it also is a topoisomerase I inhibitor, unlikecamptothecin and topotecan, CPT-11 has limited antitumor activityin vitro. In vivo, it is converted to 7-ethyl-10-hydroxy-camptothecin(SN-38), a metabolite with a 100-fold greater antitumor activitythan CPT-11 in vitro. This agent has antitumor activity againstsmall-cell and non-small-cell lung cancer, gynecologic and gastrointestinaltumors, and leukemia and lymphoma. Until recently, severe sideeffects, such as leukopenia and diarrhea, had limited its clinicaldevelopment.

In a recently reported phase II trial, irinotecan was administeredto patients with metastatic breast cancer who had undergone minimalor no prior chemotherapy [28]. The agent was administered intravenouslyover 30 minutes at a dosage of 350 mg/m² every 3 weeks. Of29 patients treated, 21 were evaluable at the time of the report;these patients had a good performance status and a moderate amountof tumor burden. Twelve patients were evaluable for response.One achieved a complete remission, whereas four others ex- periencedno 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%) of65 patients responded to irinotecan treatment [29]. No informationis available about the duration of treatment or the effect ofcamptothecin analogs on quality of life.

Elliptinium Analogs

Elliptinium acetate is a plant alkaloid developed more than 20years ago. Initial clinical evaluation demonstrated antitumoractivity against breast, kidney, and other cancers [30,31]. Althoughthe drug was of interest because of its activity and lack of myelosuppressivetoxicity, other side effects (hemolytic anemia and renal failure)aborted its clinical development. More recently, novel semisyntheticanalogs, with molecular modifications suggesting that the severedose-limiting toxicities of the parent compound would be absent,have entered phase I clinical trials [32]. Extended evaluationof these compounds is awaited with interest.

New Antifolates

Several new antifolates have been developed over the past decade[33]. Trimetrexate and edatrexate have been evaluated extensivelyin patients with breast cancer. Lometrexol is at an earlier stageof development; its antitumor activity cannot yet be quantifiedfor patients with breast cancer [34]. These agents target dihydrofolatereductase, and inhibition of this enzyme is their major mechanismof action. At this time, the most successful compound in clinicaldevelopment appears to be edatrexate (10-EDAM) (Table 4). Thisagent has marked antitumor activity against metastatic breastcancer, with tolerable toxicity [34a-37]. However, because itstoxicity is not completely predictable, additional clinical trialsin which edatrexate is combined with folinic acid are ongoing.Trimetrexate has shown evidence of antitumor activity, albeitmore modest than that observed with edatrexate [38,39].

Gemcitabine

Gemcitabine (Gemzar) is a water-soluble deoxycytidine analog and,therefore, a pyrimidine antimetabolite. It inhibits DNA synthesisand has a longer intracellular accumulation phase than cytarabine,a related compound. Gemcitabine has demonstrated antitumor activityin ovarian, head and neck, pancreatic, and non-small-cell lungcancer[40,41].

Phase I studies of gemcitabine have demonstrated that 1,200 mg/m²/wkfor 3 of every 4 weeks is an appropriate dosage for phase II studies.A phase II evaluation of this agent following this dose and scheduleof administration was completed in 44 patients with minimallytreated metastatic breast cancer [42]. Nine (29%) of the evaluablepatients achieved a partial response. Toxicity included neutropenia,liver function abnormalities, nausea, vomiting, lethargy, andalopecia. Overall, treatment was well tolerated, and confirmatorytrials are ongoing. Based on these early results, gemcitabine-basedcombinations have been developed, and their evaluation in patientswith breast cancer has been initiated. Gemcitabine was recentlyapproved by the FDA for the treatment of advanced and metastaticpancreatic cancer.

Miltefosine

Synthetic phospholipids have antitumor activity, although theirmechanism of action is not well defined [43]. They are known toinhibit protein kinase C, an essential step in the growth factorsignal transduction in cellular proliferation. Miltefosine (hexadecylphosphocholine)has marked antitumor activity in vitro and in vivo. It differsfrom other synthetic phospholipids in its lack of a glycerol backbone.Miltefosine is used as a 6% solution in an aqueous 3-alkyloxypropyleneglycol mixture. With oral administration of miltefosine in preclinicalstudies, hyperplastic gastrointestinal tract changes, gonadalatrophy, hair loss, and ocular toxicity were observed; however,no systemic effects have been observed after dermal application.

Phase II studies performed in patients with breast cancer metastaticto skin demonstrated substantial antitumor activity (Table 5)[44-47]. In some of these trials, miltefosine was employed simultaneouslywith other anticancer therapy, including chemotherapy or hormonetherapy. Because of the lack of systemic effects of miltefosine,these combinations can be accomplished without added toxicity.However, because combination studies are more difficult to assess,the antitumor efficacy of miltefosine as part of a combinationremains undefined. Additional clinical trials of the compoundare ongoing, including phase II and phase III trials. In the UnitedStates, clinical trials of miltefosine have not yet begun.

Vinca Alkaloids

The vinca alkaloids vincristine (Oncovin) and vinblastine (Velban)have been available for the treatment of breast cancer for severaldecades. The existing data suggest that vinblastine is more effectivethan vincristine [48]. In fact, after first-line therapy, vincristinehas no demonstrable antitumor activity (at currently used dosageschedules), whereas vinblastine retains substantial efficacy.

Vindesine (Eldesine) underwent clinical trials more than a decadeago; it was shown to have an efficacy similar to that of vinblastine[48]. However, vindesine was never approved by the FDA in theUnited States because available evidence did not suggest a bettertherapeutic ratio than that offered by vinblastine.

Approximately 10 years ago, vinorelbine (Navelbine), a norvinblastinederivative, underwent clinical trials.49 The most successful scheduleof administration was a short intravenous infusion, repeated weekly.Phase II studies were initiated at 30 mg/m²/wk. In most studies,the actual dosage administered varied from 20 to 25 mg/m²/wk.Tolerance was excellent, with minimal nausea or vomiting, mildalopecia, rapidly reversible myelosuppression, and minimal neurotoxicity.The efficacy of this agent in first-line and second-line therapyfor metastatic breast cancer is shown in Table 6 [50-57]. Theactivity of vinorelbine as a single agent in first-line therapyfor metastatic breast cancer appears equivalent to that of themost effective single agents available today [58]. It retainssubstantial activity in second- and third-line treatment, althoughfor anthracycline-refractory disease, it is less efficacious [59]. Because of its excellent tolerance, this agent has been usedsuccessfully for the management of elderly patients and of patientswith significant comorbid conditions.

Taxanes

Paclitaxel--Paclitaxel (Taxol) was identified and studiedin the laboratory more than 2 decades ago [60]. It is derivedfrom the bark of the western yew

(Taxus brevifolia). As a tubulin-active agent, it enhancestubulin polymerization and stabilizes microtubules. Paclitaxelhas a broad spectrum of activity against solid tumors.

Multiple schedules of administration were tested in phase I trials,but phase II studies were initiated mostly with a 24-hour infusionschedule, with cycles repeated every 3 weeks. Subsequently, otherschedules of administration were added, including 3-hour administrationand a 96-hour administration every 3 weeks [61,62]. With demonstratedantitumor activity against non-small-cell carcinoma of the lungs,head and neck cancer, ovarian cancer, and other solid tumors,paclitaxel was also shown to have marked antitumor activity againstmetastatic breast cancer. Its efficacy, according to the extentof prior treatment of disease, is shown in Table 7 [61,63-70].The agent retains considerable activity after prior chemotherapyexposure, including anthracycline-resistant tumors [62,67,69].Paclitaxel is currently being evaluated in combination chemotherapy[71].

Docetaxel--A second taxane, docetaxel (Taxotere), has alsobeen developed in recent years. It was recently approved by theFDA for anthracycline-resistant advanced or metastatic breastcancer. Structurally, docetaxel is quite similar to paclitaxel[68]. In preclinical studies, the spectrum of antitumor activityof the two taxanes is slightly different, and, in some models,docetaxel appears to be more effective than paclitaxel[72,73].

Phase I studies suggested that 100 mg/m² of docetaxel administeredover 1 hour every 3 weeks was the appropriate phase II dose andschedule of administration. Phase II trials in patients with previouslyuntreated metastatic breast cancer showed substantial antitumoractivity (Table 8) [74-76]. Considerable activity is obtained,even in strictly defined anthracycline-resistant groups [77-80].Both taxanes are currently under evaluation in combination withdoxorubicin, fluorouracil, cyclophosphamide (Cytoxan, Neosar),vinorelbine, cisplatin (Platinol), edatrexate, and many otheragents.

The dose-limiting toxicity of both taxanes is severe, but neutropeniais rapidly reversible. Hypersensitivity reactions occur frequentlywith paclitaxel but can be eliminated almost completely with athree-drug premedication regimen, including dexamethasone, diphenhydramine,and cimetidine [71]. Although hypersensitivity reactions occurmuch less frequently with docetaxel than with paclitaxel, a currentpremedication regimen often used for this drug includes 3 to 5days of corticosteroids; this is performed mostly to prevent,or decrease the incidence and severity of, skin toxicity and fluidretention. Other commonly observed side effects include myalgia,arthralgia, and peripheral neuropathy (paresthesias) with paclitaxel;onycholysis, peripheral edema, as well as the development of serosaleffusions commonly occur with docetaxel.

Conclusions

Between the registration of doxorubicin in the mid-1970s and paclitaxeland docetaxel in the 1990s, no additional new and active drugshave been approved in the United States with metastatic breastcancer as an indication. Although cisplatin has marked antitumoractivity as first-line therapy for metastatic breast cancer, thisagent has never been registered for use in breast cancer.

Over the past 5 years, the new cytotoxic agents described herehave entered into clinical evaluation. All agents have demonstratedactivity against metastatic disease, and several agents are currentlyundergoing phase I, phase II, and phase III evaluation in combinationtherapy as well as part of multimodality treatments of primarybreast cancer. Whether the marked degree of activity shown forseveral of these agents is a real difference over that of drugsdeveloped in the 1970s and early 1980s, or is simply a reflectionof changes in methodology (including the performance of phaseII and phase III studies in previously untreated patients) isdifficult to ascertain.

It is even more difficult to define the most appropriate settingin which to employ these agents in the management of breast cancer.Certainly, vinorelbine and paclitaxel have been integrated successfullyinto the second-line management of breast cancer[71,81], although,at this time, vinorelbine has not been approved by the FDA foruse in metastatic breast cancer. Single-agent vinorelbine andsingle-agent paclitaxel have also been used for the managementof patients with untreated metastatic breast cancer, especiallypatients who are elderly or patients who have comorbid conditionsthat preclude the use of anthracyclines or combination chemotherapy.However, whether combinations of these drugs are truly more effectivethan single agents utilized at the maximum tolerated dose needsto be determined. Furthermore, the effect of single agents, orcombinations based on these agents, on response rate, responseduration, survival, and quality of life must be ascertained.

It is unlikely that any of these agents alone will change thenatural history of metastatic breast cancer. Therefore, the optionsto be explored include adding these single agents to existingcombinations (cyclophosphamide, methotrexate, fluorouracil [CMF];or fluorouracil, Adriamycin, cyclophosphamide [FAC]), substitutingthese agents for other agents in existing combinations, or developingentirely new combinations of agents listed in Table 1. These newcombinations must then be compared with existing and commonlyused combinations to determine which one(s) will become the treatmentof choice for untreated patients with metastatic breast cancer.The availability of these many new, active, and well-toleratedcytotoxic agents provides a tremendous opportunity to review theimpact of chemotherapy on metastatic breast cancer; through thisprocess, we may learn the best way to integrate these compoundsinto the curative treatment of primary breast neoplasms.

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