Integration of Docetaxel Into Adjuvant Breast Cancer Treatment Regimens

ABSTRACT: Adjuvant chemotherapy is an integral component of the multidisciplinary curative treatment of primary breast cancers. The experience of the last 3 decades indicates that anthracycline-containing regimens provide the most effective cytotoxic treatment for this purpose. The development of the taxanes over the past 10 years represents substantial progress, and taxane-containing regimens are widely used for the treatment of metastatic breast cancer. Most ongoing clinical trials of adjuvant chemotherapy include a taxane-related question. The docetaxel (Taxotere)-containing regimens were developed following one of three important strategies: (1) the sequential administration of docetaxel to existing, commonly used combinations; (2) the simultaneous addition of docetaxel to an existing regimen; and (3) the substitution of docetaxel for one of the drugs included in standard combinations. These three approaches are under intense investigation by large multicenter, multinational clinical trials. The results of these phase III, prospective, randomized trials will establish the contribution of docetaxel to the curative treatment of breast cancer and will determine the optimal method of incorporating this drug into standard adjuvant therapy. [ONCOLOGY 16(Suppl 6):27-33, 2002]

The introduction of adjuvant chemotherapy intotreatment was based on improved understanding of the natural history andclinical course of breast cancer managed surgically during the first half of the20th century.[1] This experience led to the increased realization thatmicrometastases were in existence in most patients at the time of initialdiagnosis.[1,2] The initial reports were based on single-agent alkylatingtherapy,[2,3] followed shortly by clinical trials that used the CMF combinationregimen of cyclophosphamide, methotrexate, and fluorouracil (5-FU) as anadjuvant therapy to surgical resection.[4] By 1980, most North Americanoncologists accepted adjuvant chemotherapy as a clinically beneficialintervention for premenopausal patients with axillary lymph node-positivebreast cancer.

The Early Breast Cancer Trialists’ Collaborative Group established adatabase of all randomized clinical trials (whether published or not) of primarybreast cancer. Meta-analyses of all available data explored the effect ofsystemic and locoregional therapies on odds of recurrence and mortality.[5-10]These meta-analyses, conducted at 5-year intervals starting in 1985, contributedsubstantially to the general acceptance of adjuvant systemic therapy as standardtreatment.[7-9,11-12] By 1985, the clinical value of adjuvant tamoxifen wasdemonstrated, and by 1990, there was evidence that extended the indications ofadjuvant chemotherapy and hormonal therapy to lymph node-negative breastcancer. A recent National Institutes of Health (NIH)-organized ConsensusDevelopment Conference on Adjuvant Therapy of Breast Cancer issued acomprehensive, evidence-based report on the status of adjuvant chemotherapy(available at http://odp.od.nih.gov/consensus/cons/114/114_intro.htm).

Individual studies, and especially the overview of randomized trials,demonstrated the value of ovarian ablation (whether surgical, chemical, orradiation-induced) in reducing risk of recurrence or death for premenopausalpatients.[5,11] The benefits from ovarian ablation appear similar to those ofadjuvant chemotherapy and persist for at least 15 years after diagnosis. As isthe case for all hormonal therapy, the benefits of ovarian ablation are limitedto women with estrogen receptor-positive breast cancer. Mature evidence fromindividual trials and the overview not only confirmed the value of tamoxifen inreducing risk of recurrence and death, but also demonstrated that the effects ofthis intervention persist 10, and probably 15, years beyond diagnosis.[5,12] Theoptimal duration of tamoxifen therapy appears to be 5 years.[13-15] For patientsof any age with estrogen receptor-positive breast cancer, the combination oftamoxifen and chemotherapy provides greater benefits than either treatmentalone.[5,12]

Review of randomized clinical trials of cytotoxic therapy prompts severalconclusions. First, combination chemotherapy is clearly more effective thansingle-agent treatment.[5,7-9,16-19] The question of whether the most effectivedrugs should be combined simultaneously, or in sequence, is currently underevaluation.[20] Second, chemotherapy appears more effective for women under theage of 50 years than for those older than age 50.[7,9] Chemotherapy has both acytotoxic and an endocrine effect in premenopausal patients, whereas theendocrine effect would be absent in postmenopausal women.[21-24] Lower thanstandard doses have been associated with inferior results.[25-27] The effect ofadjuvant chemotherapy in women older than age 70 years has not been adequatelytested.

The estrogen receptor status of the tumor is another factor that modifies theeffect of adjuvant chemotherapy. There is a trend towards greater reductions inodds of recurrence and death for estrogen receptor-poor primary tumors thanfor estrogen receptor-rich tumors.[7-9] These differences are observed in bothyounger and older patient groups.

While several drugs and drug combinations have been used for adjuvantchemotherapy, most first-generation clinical trials utilized a combination ofcyclophosphamide, methotrexate, and 5-FU (CMF). Evidence from second-generationtrials supported the use of anthracycline-based therapy as the treatment ofchoice for most patients.[9] The use of doxorubicin (Adriamycin) or epirubicin (Ellence)in combination with other agents provided greater benefit than combinationswithout anthracyclines.[28]

The AC regimen (doxorubicin [Adriamycin]/cyclophosphamide [Cytoxan, Neosar])has been readily adopted in North America because of its ease of administration.There is no evidence, however, that this regimen is any better than CMF or thatit is equivalent to more widely tested combinations, such as FAC (fluorouracil[5-FU]/doxorubicin [Adriamycin]/cyclophosphamide [Cytoxan]) or FEC(5-FU/epirubicin/cyclophosphamide), each of which has been shown to be superiorto the classic CMF regimen (http://odp.od.nih.gov/consensus/cons/114/114_intro.htm).

Regardless of the regimen used, four to six cycles of therapy provide optimalresults when using one, nonsequential combination; shorter treatment durationsmight be less effective.[29,30] Fixed crossover regimens, using two differentcombinations, are under evaluation today and require longer durations oftreatment.[31-33]

The Role of Taxanes in Adjuvant Therapy

The role of taxanes in the adjuvant therapy of breast cancer is under intenseinvestigation. Two consecutive analyses of a large randomized Cancer andLeukemia Group B trial (CALGB 9344) in node-positive patients designed to testwhether four cycles of paclitaxel following four cycles of AC improved theresults of four cycles of AC demonstrated a small but significant reduction inodds of recurrence and death for the paclitaxel-containing arm. The results ofthe third analysis of this trial, presented at the recent Consensus DevelopmentConference, showed a quantitative reduction in this benefit, while thequalitative advantage persisted for the paclitaxel-treated group. Resultsdemonstrate that the absolute differences in recurrence rates and survival rateswere maintained, but relative improvement in survival end points are becomingless significant. Two other randomized trials (National Surgical Adjuvant Breastand Bowel Project [NSABP] and The University of Texas M. D. Anderson Cancer Center) also designed totest the role of taxanes in the adjuvant chemotherapy of breast cancer, failedto show, as yet, a significant advantage for the paclitaxel group.

A policy of optimal locoregional therapy combined with ananthracycline-containing chemotherapy regimen and hormone therapy targeted topatients with hormone receptor-positive tumors should result in a 40% to 60%relative reduction in risk of recurrence and a 40% to 50% relative reduction inmortality when compared with surgical therapy alone. While this representssubstantial progress, there is still much room for improvement. Therefore,incorporation of new and effective antitumor agents into the curative regimensused for adjuvant systemic therapy is a very high priority.

Docetaxel in Adjuvant Chemotherapy of Breast Cancer

Docetaxel (Taxotere) is a tubulin-active antitumor agent with substantialactivity against breast cancer.[34-36] When used as a single agent, docetaxelproduces overall response rates ranging from 50% to 70% in groups of patientspreviously unexposed to chemotherapy; in anthracycline-resistant patients,docetaxel retains a high level of activity, with response rates exceeding 40% inseveral studies. In randomized clinical trials, the activity of docetaxelexceeds that of doxorubicin, previously considered to be the most effective drugagainst breast cancer.[37] It is, therefore, imperative to evaluate thecontribution of this drug to adjuvant chemotherapy and to determine the optimalway to incorporate it into standard therapy for primary breast cancer. Below isa review of the potential strategies to incorporate docetaxel into adjuvantchemotherapy of breast cancer.

Sequential Combination With Anthracycline-Based Regimens

The simpleststrategy is to add several cycles of single-agent docetaxel after completing theplanned anthracycline-containing regimen. This design is similar to that used byCALGB 9344 and NSABP B-28 to determine the efficacy of paclitaxel in adjuvanttreatment.[38] The French Cooperative Group uses the same design but comparesthe same number of chemotherapy cycles (six vs six) rather than a differentnumber of chemotherapy cycles (eg, four vs eight) (Table1). The EasternCooperative Oncology Group (ECOG) trial E1199 also uses this approach butcompares taxane-containing arms without a control arm.

Currently, there are two competing hypotheses about drug combinations beingtested both in metastatic and primary breast cancer. The first, with over 30years of experience to support it, is based on the Goldie-Coldman hypothesis andthe earlier work of Skipper and Schabel.[39-42] It calls for the simultaneousadministration of two or more drugs at the maximum tolerated doses for thecombination. The second, based on the Norton-Simon hypothesis, calls for thesequential administration of single-agent therapy, also at the maximum tolerateddoses.[43,44]

This second hypothesis was developed at the time when it was believed thatdose and dose-intensity were major determinants of outcome, and, therefore, theadministration of each cytotoxic drug at the maximum tolerated single-agent dosewas of the utmost importance.[45,46] Clinical trials performed over the pastdecade have suggested that dose and dose intensification are not majordeterminants of outcome for the most important drugs in the treatment of breastcancer (taxanes, anthracyclines, alkylating agents).[32,47-49] Therefore,continued testing of these two hypotheses may provide information primarilyrelated to quality of life, rather than leading to improvements in outcome.

Some of the trial designs call for single-agent docetaxel to be administeredsequentially before or after other commonly used cytotoxic agents (doxorubicin,epirubicin, cyclophosphamide). Regardless of the hypothesis being followed, itis likely that all regimens in which single-agent docetaxel is addedsequentially to other drugs or drug combinations will result in similaroutcomes. The conglomerate of these studies will define whether the addition ofdocetaxel to "standard" adjuvant chemotherapy provides an improvementin relapse-free and overall survival rates.

Simultaneous Combinations With Anthracycline-Based Regimens

Anotherapproach to incorporating a new drug into the management of primary breastcancer is to add it to existing regimens. This approach is based on theassumption that the new drug is independently effective against the tumor beingtreated, that it lacks complete cross-resistance with the other drugs includedin the combination, and that the toxicities of the new and old agents are notcompletely overlapping. Since existing drugs given in combination already employthe maximum tolerated doses of each drug in the combination, it is likely thatthe addition of another drug (in this case, docetaxel) will require a modestreduction in doses for the "standard" drugs as well as for the"new" drug.

The NSABP B-30 and Breast Cancer International Research Group (BCIRG) 005trials are protocol designs representative of this approach. These clinicaltrials will determine whether the addition of a third drug will improve thetherapeutic effect of the combination sufficiently to exceed the probabledecrease in efficacy because of necessary dose reductions, and whether theimproved efficacy will compensate for increases in toxicity. Should thisstrategy be successful, it would lead to the development of shorter and moreeffective regimens than the previously described strategy; the sequentialaddition of docetaxel, on the other hand, would lead, by force, to theprolongation of adjuvant chemotherapy programs.

Substitution for Another Drug in an Established Chemotherapy Regimen

Athird conceptual approach to incorporating docetaxel in adjuvant chemotherapy ofbreast cancer is to take an existing combination, remove one of the drugs, andincorporate docetaxel instead. The advantage of this approach is that, ingeneral, no dose reductions for the remaining components of the originalcombination are needed. However, this approach assumes that docetaxel is moreeffective than the drug being dropped from the original combination and thuswill improve the efficacy of the regimen. Representative clinical trialsexploring this strategy are included in the bottom section of Table1. Of note,the NSABP B-30 protocol compares all three strategies for introducing docetaxelinto adjuvant therapy (Figure 1). While this three-arm trial will determinewhether any of the approaches is superior to the others, there is no"control" arm (ie, a treatment arm without docetaxel).

The results of the planned interim analysis of the BCIRG 001 trial comparingTAC (docetaxel [Taxotere], doxorubicin [Adriamycin], cyclophosphamide) with FACare available (Figure 2).[50] At 33 months, TAC showed an overall improvement indisease-free survival (32% risk reduction, P =.001, log-rank analysis), thestudy’s primary end point. A 29% reduction in mortality was also observed (P =.049, multivariate COX analysis). A prospective analysis by nodal statusrevealed a 50% reduction in relapse rate (P = .0002) and a 54% reduction inmortality rate (P = .0006) in patients with one to three positive nodes.Additional follow-up will confirm these results and the appropriate integrationof TAC in the adjuvant setting.

Whereas docetaxel was shown to be superior to doxorubicin in a phase IIItrial and, by inference, is considered to be one of the most effective agentsagainst breast cancer, there is limited information about its comparativeefficacy in relation to other commonly used anticancer agents. This thirdstrategy is particularly attractive in the specific situation of patients withHER2/neu-overexpressing breast cancers, however.[51]

Our increased understanding of the biology of breast cancer led to thedevelopment of a specific intervention for the treatment of HER2/neu-overexpressingbreast cancers.[52,53] Trastuzumab [Herceptin], the monoclonal antibody thatbinds with a high degree of affinity to the extracellular domain of the Her2oncoprotein and thus interferes with HER2 signaling, has been shown to havesubstantial antitumor activity in HER2/neu-positive tumors.[54] When added tocytotoxic therapy, it improves response rate, time to progression, andsurvival.[55,56]

However, trastuzumab in combination with doxorubicin leads to cardiactoxicity in 27% of patients, including an almost 10% incidence of congestiveheart failure.[55] Thus, although randomized trials indicated thatanthracycline-containing regimens are the most effective cytotoxic treatment forprimary breast cancer, there is intense interest in developing non-anthracycline-containingregimens for patients with HER2/neu-positive tumors.[57] Such a combinationwould reduce the risk of cardiac toxicity to a minimum.[38]

The absence of an anthracycline in the adjuvant therapy of HER2/neu-overexpressingtumors is problematic, however, since several retrospective analyses suggestthat anthracyclines are clearly an important component of the treatment ofpatients with HER2/neu-positive tumors.[58-63] This strong belief in the need touse anthracyclines for the treatment of HER2/neu-positive tumors is alsoreflected in the fact that the only trial to date that includes a non-anthracycline-containingarm in the adjuvant therapy of HER2/neu-positive tumors is BCIRG 006 (Figure3).The BCIRG 006 trial design will test the nonanthracycline regimen of docetaxel,carboplatin [Paraplatin]), and trastuzumab, a combination that demonstrated asynergistic interaction in breast cancer modeling studies.[64] All remainingcompleted or ongoing trials attempt to minimize the risk of cardiac toxicity byavoiding the simultaneous administration of the anthracycline and trastuzumab,by using a less cardiotoxic anthracycline (liposomal anthracyclines orepirubicin), or by adding a cardioprotector agent such as dexrazoxane (Zinecard)to the combination.

Conclusions

The development of docetaxel was a major contribution to our therapeuticarmamentarium. Currently, multiple clinical trials are recruiting patients toassess the contribution of this active drug to the curative management of thisdisease. The inclusion of taxanes, newer hormonal therapies, trastuzumab,bisphosphonates, and other, biologically based interventions is expected tofurther improve the prognosis of patients with breast cancer. Clinical researchin this area should continue, grounded in sound biological principles, optimaltrial methodology, and enhanced participation by physicians and patients alike.Our markedly expanded understanding of the biology of breast cancer, along withthe development of novel targets and corresponding therapeutic agents, providesus with enhanced opportunities for improved results.

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