Combinations of New and Old Agents for Breast Cancer Treatment: Future Directions
Combinations of New and Old Agents for Breast Cancer Treatment: Future Directions
For 15 years after the registration of doxorubicin in most western industrialized countries, developmental chemotherapy for breast cancer has consisted of the reutilization of multiple existing cytotoxic agents in different combinations and dose schedules . 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 the most effective and most commonly used for the management of metastatic breast cancer [1-6]. However, overall response rates, complete remission rates, remission duration, and duration of survival for previously untreated patients with metastatic breast cancer and for previously treated patients with metastatic breast cancer remained unchanged. The introduction of dose intensification has yet to prove its ability to affect survival [7-9].
Therefore, it was gratifying to see a number of new and effective cytotoxic agents introduced into clinical trials over the past 5 to 10 years. Phase II and limited phase III studies have demonstrated the marked antitumor efficacy of the anthrapyrazoles [10-12], edatrexate [13-15], topotecan  and irinotecan [17,18], gemcitabine (Gemzar) , the taxanes [20-24], and vinorelbine (Navelbine) [25-30]. The challenge now is to incorporate these agents into the 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 with these new agents and "older" agents is daunting.
There are some basic principles on which the development of combination chemotherapy is based
- The individual agents considered for the combination must have independent antitumor activity against the tumor being treated.
- There is minimal or no overlapping toxicity.
- There is no known antagonistic interaction among two or more of the agents being considered for the combination.
For any specific new drug, the challenge is to determine the best way to integrate it into the management of a particular tumor type. 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 substantial investment of time and resources to test clinically. With the availability of many new and active drugs, the number of permutations increases exponentially, and the difficulties in establishing a role for each agent in the standard management of breast carcinoma are multiplied many-fold.
Anthrapyrazoles, Camptothecin Analogs, Edatrexate, and Gemcitabine--Table 2 offers combinations under evaluation for the anthrapyrazoles, camptothecin analogs, edatrexate, and gemcitabine [31-34] Information about these combinations is limited and follow-up short, but it is apparent that several of them have substantial antitumor activity, comparing favorably with that of previously existing standard combination chemotherapy. Other combinations of these agents are in phase I trials; however, either no patients with breast cancer were included or the intent was clearly to develop these combinations for evaluation in other tumors. Any combination that includes these drugs and other active drugs against breast cancer would be of interest to evaluate in breast carcinoma in humans. No combination trial reports were found for teloxantrone or piroxantrone. Based on the available data, it is impossible to assess whether these combinations are of equal or higher efficacy than that of standard combination chemotherapy for metastatic breast cancer (FAC or CMF).
Paclitaxel- and Docetaxel-Based Combinations--Table 3 similarly describes several paclitaxel (Taxol)- and docetaxel (Taxotere)-based combinations [35-48]. These agents have been under evaluation internationally for 4 years; thus, there is more information available about their single-agent activity and about the activity of each drug in combination with several old and new agents [35-48]. Many more combinations based on paclitaxel are currently in clinical trials, and other docetaxel-based combinations are under evaluation, but no preliminary reports are yet available. The combinations included in Table 3 represent those that appear to be the most active, based on available published data. However, this information is 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 least as effective as FAC or CMF, with the possibility that some of the 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 evaluation is necessary and that strategies to reduce the frequency and severity of toxic effects must be explored and instituted.
Vinorelbine-Based Combinations--Table 4 describes combinations based on vinorelbine[49-62]. Of all the new drugs, vinorelbine was introduced into clinical trials first, making the clinical experience with this new agent the richest. Combination therapy with vinorelbine has included all the major and most effective older drugs and some of the newer agents described elsewhere in this issue. Vinorelbine combinations also appear to be as effective as standard combinations. Although there is no evidence that the efficacy of vinorelbine combinations is greater than that of FAC or 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 obvious difference in efficacy among combinations that include old and new agents or among combinations of new agents only. What is apparent is that a large number of new, effective combinations are being developed. Establishing the role of each combination in breast cancer management is the next challenge.
New Drug Added to "Old" Agent--Most new combinations contain an effective "old" drug and a new drug. Examples of 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 combinations is to improve the efficacy of existing combinations by substituting a new drug for an old one. Thus, the doublet paclitaxel + doxorubicin is an attempt to improve on doxorubicin + cyclophosphamide or doxorubicin + 5-fluorouracil combinations. These two-drug combinations have certainly been successful.
Entirely New Combinations--A different option is to develop entirely new combinations. Examples of this strategy include paclitaxel + vinorelbine, docetaxel + vinorelbine, edatrexate + paclitaxel, and losoxantrone + paclitaxel. A potential application of the use of all new agents in combination is the development of treatment strategies whereby the new combination is used in addition to existing, older combinations. With this strategy, fixed crossover combinations or alternative schedules of administration of new and old regimens could be developed. An example of this approach is offered in Table 5. The hypothesis behind such strategies is that the new combinations represent non-cross-resistant regimens, which will be cytotoxic to tumor cells resistant to the first combination being used.
Other Chemotherapeutic Regimens--The strategy of alternating chemotherapeutic regimens has been used against metastatic breast cancer for the past 3 decades [63,64]. Unfortunately, there is no evidence from published trials that this strategy is more effective than the continuous use of a single combination. Fixed crossover regimens have also been tried. Their efficacy against metastatic breast cancer appears to be similar to that of single combination regimens. However, there is some evidence that in the adjuvant setting, their efficacy might be superior to that of a single adjuvant chemotherapeutic combination [65,66]. Therefore, there is substantial reason to develop these combinations and evaluate their relative efficacy.
Regimens with higher efficacy, even when accompanied by increased toxicity, might be used optimally as short induction regimens. For instance, this would be an appropriate option to induce a high percentage of complete remissions before high-dose chemotherapy and autologous stem cell rescue. In this manner, the maximum benefit of a relatively toxic combination with limited toxicity would be obtained.
Combinations--With a staggering number of potential new combinations, how should particular combinations be chosen for additional clinical testing? One approach suggests that only the most successful combinations should proceed to phase III trials. However, on what criteria would this success be based? Response rates are notoriously unreliable and vary substantially from center to center and group to group, depending on patient characteristics. Survival of breast cancer is seldom modified by a single treatment regimen, and it might be unrealistic to expect major survival modifications from most new combinations. Similar problems apply to remission duration and time to progression, outcome measures heavily influenced by patient characteristics and response data. However, combinations that reproducibly yield higher-than-average (more than 75%) overall remission rates, higher-than-average (more than 30%) complete remission rates, and longer-than-expected (less than 12 months) remission durations deserve additional evaluation and systematic comparison with FAC or similarly effective standard regimens.
Another approach would be to base the selection process on proposed mechanisms of action and mechanisms of resistance of the agents included in the "new" combination. In this model, combinations consisting of new members of "old" cytotoxic families (ie, a new alkylating agent or a new anthracycline) would have a lower priority for clinical development than drugs with novel mechanisms of action (eg, taxanes or topoisomerase I inhibitors). This strategy assumes that drugs with new mechanisms of cytotoxicity would be more effective additions to the armamentarium than new analogs of existing, effective drugs. Unfortunately, there is no strong evidence to support this assumption.
Fixed crossover designs would also be appropriate to test. Although alternating schedules of administration are conceptually attractive, it is unlikely that they will have a substantial impact on the natural history of metastatic breast cancer until combinations with complete remission rates in excess of 50% are developed.
Single Agents--Combination chemotherapy is certainly not the only approach available to integrate new drugs into overall management strategies. Cytotoxic agents with substantial antitumor activity (vinorelbine, taxanes, and anthrapyrazoles) might be best used as single agents, administered at their maximally tolerated dose. For agents with a steep dose-response curve, this approach might be preferable to combination therapy, to avoid compromising the 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-dose single-agent therapy might be as effective, and less toxic, than combinations based on the same drug. This approach cannot profit from drug synergy, nor is it likely to be as effective as combination therapy in preventing the emergence of drug-resistant cell clones. However, it is a strategy that must be evaluated through clinical trials, as should all other approaches to drug integration.
Need for International Coordination--Regardless of the approach undertaken, some mechanism of international coordination would be highly desirable to avoid duplication of effort and to standardize, as much as possible, the methodology for evaluating the therapeutic index of novel combinations. Such coordination could 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 investigators worldwide on the Internet and through state-of-the-art electronic technology. At the same time, agreement on a few basic standards to enhance the quality of clinical research studies could make the development of these new combinations substantially more efficient.
Despite the absence of sufficient comparative data on new combinations versus standard chemotherapeutic regimens, several new drugs, or combinations that contain new drugs, have been introduced into adjuvant and/or neoadjuvant chemotherapeutic settings. This might be slightly premature because of the concern related to the long-term effects of any new drug introduced into clinical oncology. However, the limited efficacy of current adjuvant chemotherapeutic programs and the promising efficacy of the new drugs and new combinations make this approach quite tempting.
Table 6 describes several existing adjuvant chemotherapeutic programs that include new agents or new combinations [1,36,71-75]. At this time, only reports of tolerance and toxicity are available from most of these studies. However, a few clinical trials, in which new drug-containing combinations were used in the preoperative (or neoadjuvant) setting, reported high response rates, including histologically documented complete remissions in some patients [73-75]. To date, adjuvant therapeutic programs based on new drugs appear to be well tolerated, and no serious or irreversible toxicity has been observed. Adjuvant chemotherapy is administered to patients with potentially curable disease. Therefore, only long-term observation will define the risk-benefit ratio of these new agents and combinations in the management of primary breast cancer.
Our knowledge and experience, based on standard chemotherapeutic regimens, suggest that secondary acute leukemias appear during the first 7 to 10 years after the administration of alkylating agent therapy [76,77]. Acute leukemias appear earlier when they are related to the administration of topoisomerase II inhibitors [78,79]. However, the development of secondary solid tumors is further delayed. Cumulative incidence curves suggest that even 15 years after the administration of standard chemotherapy, there is a continued increase in the development of second primary tumors [80,81]. Therefore, the introduction of a potentially carcinogenic new drug into adjuvant therapy today will not be expected to produce its full effect until the year 2010 or beyond.
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