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
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
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
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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