Combinations of New and Old Agents for Breast Cancer Treatment: Future Directions

ABSTRACT: Several new agents undergoing clinical development appear to be effective and tolerable in the management of metastatic breast cancer. In recent years, a number of new and exciting combinations have been described, with an efficacy similar or, in some cases, apparently superior to that of standard chemotherapeutic regimens, such as FAC and CMF. The next several years will witness a large number of comparative clinical trials, the major purpose of which will be to establish the role of these new drugs and combinations in the management of metastatic breast cancer. Almost simultaneously, similar strategies will be pursued for adjuvant therapy for primary breast cancer, with the goal of improving the curative efficacy of current regimens. These prospects are exciting; however, enthusiasm must be tempered with the knowledge that long-term toxicity is always a distinct possibility. Therefore, the development of new combinations, especially in the setting of adjuvant chemotherapy, should follow a systematic, conservative strategy. [ONCOLOGY 10(Suppl):30-36, 1996]

Introduction

For 15 years after the registration of doxorubicin in most westernindustrialized countries, developmental chemotherapy for breastcancer has consisted of the reutilization of multiple existingcytotoxic agents in different combinations and dose schedules[1]. The leading combinations (fluorouracil [5-FU], Adriamycin,and cyclophosphamide [FAC]; and cyclophosphamide, methotrexate,and 5-FU [CMF]) and the less commonly used alternatives (cyclophosphamide,Novantrone, 5-FU [CNF]; Novantrone, 5-FU, calcium leucovorin [NFL];and mitoxantrone, methotrexate, mitomycin [MMM]) remained themost effective and most commonly used for the management of metastaticbreast cancer [1-6]. However, overall response rates, completeremission rates, remission duration, and duration of survivalfor previously untreated patients with metastatic breast cancerand for previously treated patients with metastatic breast cancerremained unchanged. The introduction of dose intensification hasyet to prove its ability to affect survival [7-9].

Therefore, it was gratifying to see a number of new and effectivecytotoxic agents introduced into clinical trials over the past5 to 10 years. Phase II and limited phase III studies have demonstratedthe marked antitumor efficacy of the anthrapyrazoles [10-12],edatrexate [13-15], topotecan [16] and irinotecan [17,18], gemcitabine(Gemzar) [19], the taxanes [20-24], and vinorelbine (Navelbine)[25-30]. The challenge now is to incorporate these agents intothe optimal management of primary and metastatic breast cancer.This task is difficult under the best of circumstances; however,the potential number of combinations that could be developed withthese new agents and "older" agents is daunting.

Basic Principles of Combination Chemotherapy

There are some basic principles on which the development of combinationchemotherapy is based

• The individual agents considered for the combination musthave independent antitumor activity against the tumor being treated.
• There is minimal or no overlapping toxicity.
• There is no known antagonistic interaction among two or moreof the agents being considered for the combination.

For any specific new drug, the challenge is to determine the bestway to integrate it into the management of a particular tumortype. Table 1 shows commonly used approaches to achieve such integration.The potential number of combinations and permutations is great,and each requires a large number of patients and a substantialinvestment of time and resources to test clinically. With theavailability of many new and active drugs, the number of permutationsincreases exponentially, and the difficulties in establishinga role for each agent in the standard management of breast carcinomaare multiplied many-fold.

Combinations Under Evaluation

Anthrapyrazoles, Camptothecin Analogs, Edatrexate, and Gemcitabine--Table2 offers combinations under evaluation for the anthrapyrazoles,camptothecin analogs, edatrexate, and gemcitabine [31-34] Informationabout these combinations is limited and follow-up short, but itis apparent that several of them have substantial antitumor activity,comparing favorably with that of previously existing standardcombination chemotherapy. Other combinations of these agents arein phase I trials; however, either no patients with breast cancerwere included or the intent was clearly to develop these combinationsfor evaluation in other tumors. Any combination that includesthese drugs and other active drugs against breast cancer wouldbe of interest to evaluate in breast carcinoma in humans. No combinationtrial reports were found for teloxantrone or piroxantrone. Basedon the available data, it is impossible to assess whether thesecombinations are of equal or higher efficacy than that of standardcombination chemotherapy for metastatic breast cancer (FAC orCMF).

Paclitaxel- and Docetaxel-Based Combinations--Table 3 similarlydescribes several paclitaxel (Taxol)- and docetaxel (Taxotere)-basedcombinations [35-48]. These agents have been under evaluationinternationally for 4 years; thus, there is more information availableabout their single-agent activity and about the activity of eachdrug in combination with several old and new agents [35-48]. Manymore combinations based on paclitaxel are currently in clinicaltrials, and other docetaxel-based combinations are under evaluation,but no preliminary reports are yet available. The combinationsincluded in Table 3 represent those that appear to be the mostactive, based on available published data. However, this informationis also limited in terms of comparative efficacy and, more important,comparative therapeutic index with older, existing combinations.

It is clear that taxane-based combinations appear to be at leastas effective as FAC or CMF, with the possibility that some ofthe newer combinations (taxane and doxorubicin or taxane and cisplatin[Platinol]) might be more effective than older, standard regimens.However, the increased toxicity observed with some of the newer,promising combinations dictates that formal, comparative evaluationis necessary and that strategies to reduce the frequency and severityof toxic effects must be explored and instituted.

Vinorelbine-Based Combinations--Table 4 describes combinationsbased on vinorelbine[49-62]. Of all the new drugs, vinorelbinewas introduced into clinical trials first, making the clinicalexperience with this new agent the richest. Combination therapywith vinorelbine has included all the major and most effectiveolder drugs and some of the newer agents described elsewhere inthis issue. Vinorelbine combinations also appear to be as effectiveas standard combinations. Although there is no evidence that theefficacy of vinorelbine combinations is greater than that of FACor CMF, the toxicity profile of these regimens appears to be excellent,and vinorelbine-based combinations might, as a matter of fact,be better tolerated than standard regimens.

Based on the data described in Tables 2-4, there is no obviousdifference in efficacy among combinations that include old andnew agents or among combinations of new agents only. What is apparentis that a large number of new, effective combinations are beingdeveloped. Establishing the role of each combination in breastcancer management is the next challenge.

Incorporating New Agents Into MetastaticBreast Cancer Therapy

New Drug Added to "Old" Agent--Most new combinationscontain an effective "old" drug and a new drug. Examplesof this strategy include vinorelbine + 5-FU, vinorelbine + doxorubicin,vinorelbine + mitoxantrone, paclitaxel + doxorubicin, paclitaxel+ cisplatin, paclitaxel + cyclophosphamide, docetaxel + doxorubicin,and gemcitabine + doxorubicin. The intent of these types of combinationsis to improve the efficacy of existing combinations by substitutinga new drug for an old one. Thus, the doublet paclitaxel + doxorubicinis an attempt to improve on doxorubicin + cyclophosphamide ordoxorubicin + 5-fluorouracil combinations. These two-drug combinationshave certainly been successful.

Entirely New Combinations--A different option is to developentirely new combinations. Examples of this strategy include paclitaxel+ vinorelbine, docetaxel + vinorelbine, edatrexate + paclitaxel,and losoxantrone + paclitaxel. A potential application of theuse of all new agents in combination is the development of treatmentstrategies whereby the new combination is used in addition toexisting, older combinations. With this strategy, fixed crossovercombinations or alternative schedules of administration of newand old regimens could be developed. An example of this approachis offered in Table 5. The hypothesis behind such strategies isthat the new combinations represent non-cross-resistant regimens,which will be cytotoxic to tumor cells resistant to the firstcombination being used.

Other Chemotherapeutic Regimens--The strategy of alternatingchemotherapeutic regimens has been used against metastatic breastcancer for the past 3 decades [63,64]. Unfortunately, there isno evidence from published trials that this strategy is more effectivethan the continuous use of a single combination. Fixed crossoverregimens have also been tried. Their efficacy against metastaticbreast cancer appears to be similar to that of single combinationregimens. However, there is some evidence that in the adjuvantsetting, their efficacy might be superior to that of a singleadjuvant chemotherapeutic combination [65,66]. Therefore, thereis substantial reason to develop these combinations and evaluatetheir relative efficacy.

Regimens with higher efficacy, even when accompanied by increasedtoxicity, might be used optimally as short induction regimens.For instance, this would be an appropriate option to induce ahigh percentage of complete remissions before high-dose chemotherapyand autologous stem cell rescue. In this manner, the maximum benefitof a relatively toxic combination with limited toxicity wouldbe obtained.

Choosing Agents for Clinical Testing

Combinations--With a staggering number of potential newcombinations, how should particular combinations be chosen foradditional clinical testing? One approach suggests that only themost successful combinations should proceed to phase III trials.However, on what criteria would this success be based? Responserates are notoriously unreliable and vary substantially from centerto center and group to group, depending on patient characteristics.Survival of breast cancer is seldom modified by a single treatmentregimen, and it might be unrealistic to expect major survivalmodifications from most new combinations. Similar problems applyto remission duration and time to progression, outcome measuresheavily influenced by patient characteristics and response data.However, combinations that reproducibly yield higher-than-average(more than 75%) overall remission rates, higher-than-average (morethan 30%) complete remission rates, and longer-than-expected (lessthan 12 months) remission durations deserve additional evaluationand systematic comparison with FAC or similarly effective standardregimens.

Another approach would be to base the selection process on proposedmechanisms of action and mechanisms of resistance of the agentsincluded in the "new" combination. In this model, combinationsconsisting of new members of "old" cytotoxic families(ie, a new alkylating agent or a new anthracycline) would havea lower priority for clinical development than drugs with novelmechanisms of action (eg, taxanes or topoisomerase I inhibitors).This strategy assumes that drugs with new mechanisms of cytotoxicitywould be more effective additions to the armamentarium than newanalogs of existing, effective drugs. Unfortunately, there isno strong evidence to support this assumption.

Fixed crossover designs would also be appropriate to test. Althoughalternating schedules of administration are conceptually attractive,it is unlikely that they will have a substantial impact on thenatural history of metastatic breast cancer until combinationswith complete remission rates in excess of 50% are developed.

Single Agents--Combination chemotherapy is certainly notthe only approach available to integrate new drugs into overallmanagement strategies. Cytotoxic agents with substantial antitumoractivity (vinorelbine, taxanes, and anthrapyrazoles) might bebest used as single agents, administered at their maximally tolerateddose. For agents with a steep dose-response curve, this approachmight be preferable to combination therapy, to avoid compromisingthe dose administered.

Some drugs are notoriously difficult to combine with other agents:witness the problems combining paclitaxel and docetaxel with doxorubicin,cisplatin, or even cyclophosphamide. In these instances, maximal-dosesingle-agent therapy might be as effective, and less toxic, thancombinations based on the same drug. This approach cannot profitfrom drug synergy, nor is it likely to be as effective as combinationtherapy in preventing the emergence of drug-resistant cell clones.However, it is a strategy that must be evaluated through clinicaltrials, as should all other approaches to drug integration.

Need for International Coordination--Regardless of theapproach undertaken, some mechanism of international coordinationwould be highly desirable to avoid duplication of effort and tostandardize, as much as possible, the methodology for evaluatingthe therapeutic index of novel combinations. Such coordinationcould begin with an international registry of clinical trials,in which all trials, regardless of sponsor, would be registered.This should be feasible and easily accessible to investigatorsworldwide on the Internet and through state-of-the-art electronictechnology. At the same time, agreement on a few basic standardsto enhance the quality of clinical research studies could makethe development of these new combinations substantially more efficient.

New Drug Combinations for Adjuvant Therapy

Despite the absence of sufficient comparative data on new combinationsversus standard chemotherapeutic regimens, several new drugs,or combinations that contain new drugs, have been introduced intoadjuvant and/or neoadjuvant chemotherapeutic settings. This mightbe slightly premature because of the concern related to the long-termeffects of any new drug introduced into clinical oncology. However,the limited efficacy of current adjuvant chemotherapeutic programsand the promising efficacy of the new drugs and new combinationsmake this approach quite tempting.

Table 6 describes several existing adjuvant chemotherapeutic programsthat include new agents or new combinations [1,36,71-75]. At thistime, only reports of tolerance and toxicity are available frommost of these studies. However, a few clinical trials, in whichnew drug-containing combinations were used in the preoperative(or neoadjuvant) setting, reported high response rates, includinghistologically documented complete remissions in some patients[73-75]. To date, adjuvant therapeutic programs based on new drugsappear to be well tolerated, and no serious or irreversible toxicityhas been observed. Adjuvant chemotherapy is administered to patientswith potentially curable disease. Therefore, only long-term observationwill define the risk-benefit ratio of these new agents and combinationsin the management of primary breast cancer.

Our knowledge and experience, based on standard chemotherapeuticregimens, suggest that secondary acute leukemias appear duringthe first 7 to 10 years after the administration of alkylatingagent therapy [76,77]. Acute leukemias appear earlier when theyare related to the administration of topoisomerase II inhibitors[78,79]. However, the development of secondary solid tumors isfurther delayed. Cumulative incidence curves suggest that even15 years after the administration of standard chemotherapy, thereis a continued increase in the development of second primary tumors[80,81]. Therefore, the introduction of a potentially carcinogenicnew drug into adjuvant therapy today will not be expected to produceits full effect until the year 2010 or beyond.

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