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Taxane/Anthracycline Combinations: Setting a New Standard in Breast Cancer?

University of California at Los Angeles, Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, California, USA

Correspondence: Jean-Marc Nabholtz, M.D., University of California at Los Angeles, Cancer Therapy Development Program, Jonsson Comprehensive Cancer Center at UCLA, Breast Cancer International Research Group (BCIRG), 10945 Le Conte Avenue, Los Angeles, California 90095-7077, USA. Telephone: 310-206-8452; Fax: 310-794-0079; e-mail: jean-marc.nabholtz{at}bcirg.com

	ABSTRACT

Top Abstract Introduction Initial Studies Combining... Phase II Studies of... Phase III Trials of... Randomized Phase III Trials... Taxanes in the Adjuvant... Discussion Conclusion References

 
Among the novel chemotherapeutic drugs introduced in the 1990s, the taxanes have emerged as the most powerful compounds in breast cancer. Both compounds, paclitaxel and docetaxel, have been evaluated in metastatic settings before adjuvant trials proceeded. Docetaxel was shown in several phase III trials to be superior, particularly in terms of survival, for salvaging polychemotherapies after failure of prior chemotherapy, including that with anthracyclines. A benefit of docetaxel was also reported when compared with doxorubicin after failure of alkylating agents. In phase III trials paclitaxel was reported to be as efficacious over 24 hours as doxorubicin 60 mg/m², while paclitaxel was significantly inferior to doxorubicin 75 mg/m² over 3 hours and was close to CMF in another trial. The role of taxanes in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging. Following several phase II studies, a phase III trial showed the significant superiority of docetaxel/doxorubicin (AT) versus doxorubicin/cyclophosphamide (AC) in terms of response and time to progression. In several phase II studies with paclitaxel (3 hours), anthracyclines in the metastatic setting showed high efficacy but produced cardiac toxicity related to a pharmacokinetic interaction between the two agents. This finding led to the implementation of metastatic strategies (phase III trials) aimed at avoiding the pharmacokinetic interaction, while the adjuvant strategies with paclitaxel focused primarily on the sequential approach (AC followed by paclitaxel). In contrast, adjuvant strategies with docetaxel/anthracycline-based programs were implemented following both sequential and combination approaches.

Key Words. Taxane • Anthracycline • Metastatic breast cancer • Doxorubicin • Docetaxel • Adjuvant

	INTRODUCTION

Top Abstract Introduction Initial Studies Combining... Phase II Studies of... Phase III Trials of... Randomized Phase III Trials... Taxanes in the Adjuvant... Discussion Conclusion References

 
Metastatic breast cancer (MBC) is essentially incurable with standard therapy, and patients with MBC have a median survival of about 2 years after documentation of metastasis [1]. As a consequence, the goals of treatment are to improve patients' symptoms while trying to maintain (or improve, in certain cases) quality of life. Prolonging survival remains a clear goal, but the role of chemotherapy in this regard is still unclear. The fact that some patients with complete responses when treated with anthracycline-containing regimens (FAC) in the first-line metastatic setting may present with long-term survival pleads in favor of the use of up-front chemotherapy for patients with potentially chemosensitive breast cancer [2]. Additionally, first-line MBC may be considered an optimal setting for testing new chemotherapies in a controlled manner to assess their capacity to induce long-term control of the disease.

The classical model in the development of new agents has historically consisted of assessing new drugs initially as monotherapy in the second-line setting, followed by first-line single-agent use before integrating them into first- and second-line combinations following the concept of adding the new best one to the best old ones. Only when this process has been completed is the new agent put on trial in the adjuvant setting

The development of chemotherapy in breast cancer has itself passed through several evolutionary stages. The 1960s saw the first attempts at single-agent therapy, followed in the 1970s by the pre-anthracycline combinations such as CMF and CMFVP [2]. The introduction of the anthracyclines led to almost two decades of activity in which combinations such as AC, FAC, FEC, and CEF were investigated and the possible role of sequential and alternating regimens was assessed, along with dose-intense and dose-dense schedules [2]. In the case of anthracyclines, a full 20 years elapsed between their first clinical use and the confirmation of their significant, although modest, role in the adjuvant treatment of breast cancer.

The emergence in the 1990s of powerful, novel compounds including in particular the taxanes paclitaxel and docetaxel brought a greater sense of urgency to the process of drug development. Nevertheless, it has taken approximately 10 years to come to a reasonable understanding of how the taxanes can be used sequentially and in combination with anthracyclines to improve the prospects of patients with advanced disease. Lately we are seeing the rapid introduction of biologic modifiers along with cytotoxic chemotherapy and hormonotherapy. For the benefit of patients, it is hoped that new models of development will be thought out in the context of multicenter and multinational cooperation which could facilitate the rapid evaluation of such novel therapeutic approaches.

Paclitaxel was the first taxane to show activity in breast cancer [3, 4]. Docetaxel was subsequently developed, and several phase II and III trials reported a high activity in first- and second-line therapy of MBC as well as in patients previously exposed or resistant to anthracyclines [5-8]. Taken together, these study results indicate that the taxanes as single agents, and docetaxel in particular, are the most active chemotherapeutic agents for the treatment of advanced breast cancer tumors. The combined use of taxanes with anthracyclines was the next logical step for the development of a highly effective chemotherapy combination. Anthracycline-taxane-containing regimens have been developed for both agents to test the integration ability of taxanes in polychemotherapy and their role in MBC, as well as to proceed to adjuvant strategies.

	INITIAL STUDIES COMBINING DOCETAXEL WITH DOXORUBICIN

Top Abstract Introduction Initial Studies Combining... Phase II Studies of... Phase III Trials of... Randomized Phase III Trials... Taxanes in the Adjuvant... Discussion Conclusion References

 
Phase I/II studies of docetaxel in combination with doxorubicin involved a number of different regimens [9-12]. The doses used and results obtained in certain of these key trials are shown in Table 1.

In the pilot study combining docetaxel with both doxorubicin and cyclophosphamide (the TAC regimen), the RR in patients with liver involvement was 82% [11] and 80% in patients with lung metastases [11].

In terms of safety, the phase I/II studies cited justified three main conclusions [9-12]. First, as might have been predicted given that both docetaxel and doxorubicin are myelosuppressive, neutropenia and its consequences were the main toxicities associated with their combination. Approximately one-third of patients presented at some stage with febrile neutropenia. However, since the duration of neutropenia was short, there were few cases of infection and no septic deaths. Second, nonhematological toxicities were relatively mild. In fact, it appears that combination therapy involving doxorubicin plus a dose of 75 mg/m² docetaxel causes fewer nonhematological adverse events than monotherapy with 100 mg/m² docetaxel, suggesting a threshold of toxicity for docetaxel between 75 mg/m² and 100 mg/m². Third, and perhaps most important, the addition of docetaxel to doxorubicin in these phase I/II trials did not result in any increase in anthracycline cardiotoxicity as confirmed by pharmacokinetic studies. The administration of docetaxel either at the same time as doxorubicin or 1 hour after it has no effect on the pharmacokinetics of the anthracycline [13, 14]. This finding has important implications, not only for use of the combination in patients with advanced disease but also for its feasibility in the adjuvant setting. The fact that docetaxel did not exacerbate the cardiotoxicity of doxorubicin was particularly important given the results of studies which had combined the anthracycline with paclitaxel.

	PHASE II STUDIES OF PACLITAXEL PLUS DOXORUBICIN

Top Abstract Introduction Initial Studies Combining... Phase II Studies of... Phase III Trials of... Randomized Phase III Trials... Taxanes in the Adjuvant... Discussion Conclusion References

 
The combination of paclitaxel with doxorubicin has also been extensively studied. Indeed, the research program involving this taxane began somewhat earlier than that involving docetaxel. Initial studies reported high efficacy, with response rates of 94% and 83% using 155-200 mg/m² paclitaxel delivered over 3 hours in combination with 50-60 mg/m² doxorubicin [15, 16]. However, the rate of congestive heart failure in both of these studies was greater than 20%. This is related to the fact that paclitaxel given as a short infusion decreases the liver clearance of doxorubicinol, leading to an increase in the area under the curve of the anthracycline [17]. This effect is sequence- and schedule-dependent, being greater if paclitaxel precedes doxorubicin and if the interval between the drugs is 1 hour or less [17].

Various attempts to circumvent the problem have been made. These include: A) extending the interval between doxorubicin and paclitaxel administration; B) limiting the cumulative exposure to doxorubicin to 360 mg/m² or less when using it in combination with paclitaxel, and C) using epidoxorubicin and extending the duration of paclitaxel infusion from 3 to 24 hours or longer [18-20]. Several phase III trials have addressed these issues and will be reviewed in this paper.

	PHASE III TRIALS OF DOCETAXEL PLUS DOXORUBICIN

Top Abstract Introduction Initial Studies Combining... Phase II Studies of... Phase III Trials of... Randomized Phase III Trials... Taxanes in the Adjuvant... Discussion Conclusion References

 
Phase II studies can be regarded as indicative. However, only phase III trials are definitive. Two pivotal phase III trials of docetaxel/doxorubicin combinations have been completed; both were international, multicenter studies.

TAX 306
Data from the TAX 306 study of doxorubicin 50 mg/m² plus docetaxel 75 mg/m² versus doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² have been presented elsewhere and are summarized here [21]. One important point to bear in mind in relation to this study is that the dose of doxorubicin given in the AC arm was 20% greater than that given to patients who received doxorubicin in combination with docetaxel (AT).

The characteristics of the 429 patients enrolled in this trial are presented in Table 2. The two arms of the study were well-balanced on demographic and disease characteristics. In both treatment groups, more than 60% of patients had visceral involvement, and more than 50% had bone metastases (Table 2).

The overall RR with AT was 60%, significantly higher than the 47% RR seen in patients randomized to AC (p = 0.012). Multivariate analysis showed that treatment with AT was a significant predictor of response (odds ratio versus AC 1.7; 95% CI 1.1-2.5).

Table 3 shows that the RR to AT was consistently superior to that seen with AC across subgroups of patients classified according to site and extent of metastases and prior exposure to chemotherapy.

View larger version (18K): [in this window] [in a new window]   Figure 1. Time to progression in patients randomized to doxorubicin plus docetaxel (AT) or doxorubicin plus cyclophosphamide (AC) (TAX 306) [21].

TAX 307
In a second phase III study (TAX 307), 484 patients with first-line metastatic disease and prior exposure to anthracycline were randomized to receive a regimen of 75 mg/m² docetaxel plus 50 mg/m² doxorubicin plus 500 mg/m² cyclophosphamide (TAC) or the FAC regimen consisting of 5-fluorouracil (5-FU) 500 mg/m² plus doxorubicin 50 mg/m² and cyclophosphamide 500 mg/m². Data from this study are awaited.

	RANDOMIZED PHASE III TRIALS OF PACLITAXEL PLUS DOXORUBICIN IN MBC

Top Abstract Introduction Initial Studies Combining... Phase II Studies of... Phase III Trials of... Randomized Phase III Trials... Taxanes in the Adjuvant... Discussion Conclusion References

 
The Intergroup/Eastern Cooperative Oncology Group 1193 trial was evaluating the use of paclitaxel given over 24 hours plus doxorubicin in comparison with either single agent (Table 5). A total of 739 patients with first-line metastatic disease were randomized to single-agent doxorubicin 60 mg/m², single-agent paclitaxel 175 mg/m² over 24 hours or a combination of 50 mg/m² docetaxel and 150 mg/m² paclitaxel, again over 24 hours [22]. Patients assigned to single agents crossed over to the alternative therapy on progression. The study was therefore additionally a comparison between combined and sequential use of taxane and anthracycline.

The study by Pluzzanka et al. was interesting in that it is the only first-line trial in MBC to compare doxorubicin plus a taxane against an anthracycline-containing arm (FAC) with a limited option of subsequent taxane salvage (Table 5) [23]. Approximately 130 patients were treated in each arm. This trial was attempting to avoid the pharmacokinetic interaction by allowing 24 hours to elapse between the administration of doxorubicin and the start of the 3-hour infusion of paclitaxel. The RR with doxorubicin plus paclitaxel was significantly higher than with FAC (68% versus 55%, p = 0.032) and the progression-free survival was longer (median 8.3 versus 6.2 months, p = 0.034). Importantly, survival was longer in patients treated with paclitaxel plus doxorubicin (22.7 months) than in those administered FAC (18.3 months), a difference significant at p = 0.02. This increase in survival in metastatic disease is an important finding, confirming the capability of taxanes to increase survival in the metastatic setting. A 20% or greater fall in ejection fraction occurred in 15% of patients treated with doxorubicin plus paclitaxel and in 10% of those receiving FAC; however, the incidence of clinical CHF was low in both arms.

In the European Organization for the Research and Treatment of Cancer (EORTC) trial 10961, patients were randomized to either doxorubicin 60 mg/m² plus paclitaxel 175 mg/m² administered over 3 hours or doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² (AC), both treatments administered q 3 weeks for a maximum of six cycles (Table 5) [24]. This trial was testing the hypothesis that cardiac toxicity could be avoided by limiting the cumulative dose of doxorubicin to 360 mg/m² (six courses maximum). The RR in the two arms were very similar: 58% with paclitaxel plus doxorubicin versus 54% with doxorubicin plus cyclophosphamide (p = NS). The median progression-free survivals were also nearly identical (6 months versus 5.9 months, p = NS). In terms of toxicity, the combination including paclitaxel was more likely to induce febrile neutropenia (which occurred in 32% of patients, compared with 9% in the AC arm). Patients assigned to paclitaxel plus doxorubicin were also more likely to experience a fall in left ventricular ejection fraction (LVEF) (27% versus 14%). This was defined as a 5% or greater absolute drop below the normal lower limit or a 10% or greater relative drop from baseline, which took the value to the lower limit of normal or below. In case of febrile neutropenia or decreased LVEF, this trial called respectively for a decrease of the doses of doxorubicin or for a discontinuation of doxorubicin. This has resulted in a significant decrease in the relative dose intensity of doxorubicin, in particular in the paclitaxel/doxorubicin arm (0.75). This could be one of the explanations for the lack of difference observed between the two arms of this trial. It may therefore be that dose reduction of the anthracycline in patients experiencing neutropenia or lowered ejection fraction has counteracted any efficacy advantage that might have been gained by combination with the taxane.

Interestingly, in TAX 306, the relative dose intensity of doxorubicin was maintained at 96% across all eight cycles and in both arms of the trial.

Finally, a German trial randomized more than 500 patients with MBC to either epirubicin 60 mg/m² plus paclitaxel 175 mg/m² over 3 hours or epirubicin 60 mg/m² plus cyclophosphamide 600 mg/m² (Table 5) [25]. Both regimens were given q 21 days for 6-10 cycles. RR in the two arms were similar (46% when epirubicin was combined with paclitaxel and 40% when combined with cyclophosphamide). Median time to progression in the two arms was 39 weeks and 32 weeks, respectively (non-significant by log-rank test), and the overall survival curves overlapped for most of their course.

	TAXANES IN THE ADJUVANT SETTING

Top Abstract Introduction Initial Studies Combining... Phase II Studies of... Phase III Trials of... Randomized Phase III Trials... Taxanes in the Adjuvant... Discussion Conclusion References

 
The first generation of adjuvant phase III trials compared a taxane/doxorubicin-based combination or sequence to a doxorubicin-containing regimen. One of the important differentiations between the two taxanes in the adjuvant setting is that docetaxel has been developed in combination (TA or TAC) as well as in sequence chemotherapy (AC followed by docetaxel), while paclitaxel was quasi-exclusively studied in sequence in order to avoid the pharmacokinetic interaction (and thus the potential cardiac toxicity) observed with the paclitaxel/doxorubicin-based combinations.

The sequential strategy has been the first to be evaluated and has led to large phase III trials in node-positive patients: AC followed by docetaxel (National Surgical Adjuvant Breast and Bowel Project [NSABP]) or AT (docetaxel) followed by CMF/A followed by T followed by CMF (Breast Adjuvant Study Team and International Breast Cancer Study Group [IBCSG]) or FEC (5-FU, epidoxorubicin, cyclophosphamide) followed by docetaxel (French Cooperative Group). Additionally, the Italian Group is studying E followed by T followed by CMF, while the International Cancer Cooperative Group (ICCG) is evaluating E followed by T. Paclitaxel has also been tested in sequence (AC followed by paclitaxel) in the CALGB 9344 trial (Cancer and Leukemia Group B) and NSABP B28 trial. Early results have suggested a moderate improvement induced by the addition of paclitaxel (175 mg/m² by 3-hour infusion) in a subgroup of patients with negative hormonal receptors.

The second strategy follows the classical polychemotherapy concept for which docetaxel-based combinations are being studied quasi-exclusively. Protocols such as TAC (docetaxel) at doses of 75/50/500 mg/m² have been compared with FAC (Breast Cancer International Research Group [BCIRG] trial 001) in patients with node-positive breast cancer or AT (docetaxel) at doses of 60/60 mg/m² to AC (Eastern Cooperative Oncology Group [ECOG]) in high-risk node-negative patients or those with one to three positive nodes. The initial results, with 36 months' median follow-up, will be available in the second part of 2001 (BCIRG 001).

In 2000, the first generation of adjuvant trials comparing docetaxel/anthracycline-based programs with classical anthracycline-containing regimens were either completed or nearing completion. The trend has been to open the next generation of adjuvant trials without waiting for these results.

The second generation of phase III studies contains taxanes in all the arms, and tests are related either to the comparison of both taxanes given in sequential strategies or the optimal use of docetaxel comparing sequence to polychemotherapy.

The American Intergroup is using the sequential approach and is comparing AC followed by either paclitaxel or docetaxel given either weekly or three-weekly in a large four-arm trial.

The sequential strategy is being directly compared with the polychemotherapy strategy by the NSABP with the B30 trial: AC (60/600 mg/m²) x 4 followed by docetaxel (100 mg/m²) x 4 versus AT (60/60 mg/m²) x 4 versus TAC (60/60/600 mg/m²) x 4. In this program, a sequence with eight courses is being compared with four courses of docetaxel/doxorubicin-based polychemotherapy using the doublet-based docetaxel/doxorubicin at 60/60 mg/m² (favoring the increased dose of doxorubicin with 60 mg/m² instead of 50 mg/m² and decreasing the dose of docetaxel from 75 mg/m² to 60 mg/m²). With the idea to further study an optimal polychemotherapy, BCIRG has developed a large phase III trial (BCIRG 005) comparing the same sequence as in the trial NSABP B30 (AC x 4 followed by docetaxel x 4) with a triple polychemotherapy (TAC) using higher doses of docetaxel (75/50/500 mg/m²) given for a total of six courses.

The second generation of adjuvant phase III trials is currently open or opening and represents the last generation of pivotal trials using taxanes in the adjuvant setting.

	DISCUSSION

Top Abstract Introduction Initial Studies Combining... Phase II Studies of... Phase III Trials of... Randomized Phase III Trials... Taxanes in the Adjuvant... Discussion Conclusion References

 
The role of taxane/anthracycline polychemotherapies in the management of MBC is still subject to controversies. Phase III trials have shown that the combination of doxorubicin 50 mg/m² and docetaxel 75 mg/m² has proven significantly superior to the combination of doxorubicin with cyclophosphamide and brings benefit in disease control without additional cardiotoxicity [21]. With data on survival still outstanding, these findings have immediate clinical relevance in the management of patients with life-threatening situations in first-line therapy of MBC. One of the most important findings reviewed concerns the high RR seen when patients with liver, lung metastases, or multiple-site disease are treated with the AT combination. In patients with rapidly progressing and life-threatening visceral disease, up-front use of docetaxel plus doxorubicin can achieve a 50% higher chance of controlling the disease as opposed to AC chemotherapy. Febrile neutropenia occurs in around one-third of patients treated with AT. Nevertheless, the rate of infection is relatively low, and the risk of septic death, according to the phase III experience, is not clinically significant given effective management.

In a subsequent phase III randomized trial, patients receiving TAC were randomized to receive one of two cytokines (one of which was G-CSF). In this study, prophylactic use of G-CSF markedly reduced the incidence of febrile neutropenia by 6.7% (Nabholtz, personal communication).

The TAX 306 data indicate that the use of doxorubicin 50 mg/m² plus docetaxel 75 mg/m² is associated with a relatively low rate (3%) of clinical CHF. The fact that this AT regimen has no more cardiac toxicity than AC (60 mg/m² doxorubicin plus 600 mg/m² cyclophosphamide) is relevant to the use of this regimen in the adjuvant setting.

After a median follow-up of more than 36 months in TAX 306, the number of deaths has not reached the level necessary (set at 85% of events) for a survival analysis to be undertaken. This may suggest a plateau in the survival curves in one or both arms of the trial. The survival results are particularly awaited, since the great majority of patients on the AC arm were subsequently treated with docetaxel at time of relapse. This will allow comparison of the up-front use of docetaxel/doxorubicin versus the sequence of AC followed by docetaxel and assessment of the possibility that the good results seen in poor prognostic patients may induce a tail phenomenon in terms of survival for the AT combination.

The phase III trials of paclitaxel in combination with doxorubicin have had mixed results. While the addition of paclitaxel to doxorubicin proved superior when compared with FAC with limited taxane salvage (a finding which has implications for the adjuvant setting), the EORTC study found that doxorubicin plus paclitaxel was not superior in efficacy to doxorubicin plus cyclophosphamide, and a similar result was found when epirubicin was combined with either paclitaxel or cyclophosphamide. The various ways of avoiding the pharmacokinetic interaction between paclitaxel given by short infusion and doxorubicin have not translated so far into convincing evidence of the superiority of this combination and have induced problems related to the lack of practicality for community use (paclitaxel and doxorubicin given in a 24-hour interval).

	CONCLUSION

Top Abstract Introduction Initial Studies Combining... Phase II Studies of... Phase III Trials of... Randomized Phase III Trials... Taxanes in the Adjuvant... Discussion Conclusion References

 
When Hayes wrote an influential paper in 1987 on standard therapy in MBC, he concluded that the best approach was still being debated [26]. Fourteen years later, that is still the case. Nevertheless, several points have become clear in the recent past: first, taxanes appear capable of improving survival in MBC; second, the combination of doxorubicin with docetaxel is superior to doxorubicin plus cyclophosphamide, particularly in poor-prognosis patients; third, of the two taxanes, only docetaxel is being tested in combination with doxorubicin, while docetaxel and paclitaxel are being studied in sequential strategies in the adjuvant setting. The results of all these trials will help us understand the magnitude by which the taxanes may change the natural history of breast cancer.

	REFERENCES

Top Abstract Introduction Initial Studies Combining... Phase II Studies of... Phase III Trials of... Randomized Phase III Trials... Taxanes in the Adjuvant... Discussion Conclusion References

 

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