Taxanes-anthracyclines in metastatic breast cancer

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Jean-Marc A Nabholtz
MD MSc
Hartmann Oncology Institute
American Hospital of Paris
Levallois-Perret
France
E:[email protected]

Among the cytotoxic agents developed during the last decade for the treatment of advanced breast cancer, taxanes have emerged as the most powerful compounds. Paclitaxel and docetaxel have substantial activity as single agents, and both drugs have been investigated in combination and sequential regimens against advanced disease and in the adjuvant setting.

According to the classical model of development, consisting of adding new agents to the “old” best ones, the most intensive efforts have focused on integrating taxanes with anthracyclines.

This review focuses on combination and sequential regimens involving taxanes with doxorubicin or epirubicin, and presents results of clinical trials using these regimens and their consequences for the management of advanced breast cancer.

Rationale for the use of taxane–anthracycline combinations
Both paclitaxel and docetaxel are now widely used for the treatment of metastatic breast cancer (MBC). Both drugs have substantial activity as single agents and have been evaluated in combination regimens for the management of early and advanced breast cancer.

Paclitaxel shows significant antineoplastic activity against a number of solid tumours.(1) Phase I and II trials were originally conducted using a variety of doses and infusion schedules, confirming a good single-agent activity against MBC, but generated confusion regarding the most effective mode of administration of the drug.

Large randomised studies suggested that a dose of 175mg/m(2) (delivered over 3h every 3 weeks) was both efficacious and tolerable. Dose escalation and the use of prolonged infusion schedules (24–96h) may yield better outcome, while data suggest that weekly or biweekly paclitaxel may compare favourably to the standard dosing regimen of every 3 weeks in terms of efficacy and toxicity.(2,3)

Single-agent paclitaxel was then compared with doxorubicin monotherapy in two phase III trials.(4,5) In one study, paclitaxel (200mg/m(2) delivered over 3h every 3 weeks) was inferior to doxorubicin (75mg/m(2))(4), while first-line paclitaxel (175mg/m(2) given over 24h) was similar to doxorubicin (60mg/m(2)).(5)

Docetaxel has also emerged as one of the most active drugs against advanced breast cancer.  Numerous phase II trials using a dose of 100mg/m(2) given every 3 weeks as a 1h infusion established the activity of docetaxel as a monotherapy; this was confirmed by a series of randomised trials.(7–9)

In these studies, docetaxel compared favourably with doxorubicin (75mg/m(2)),(6) while showing significant superiority to various salvage regimens after prior exposure to anthracyclines.(7–9) These results positioned this agent as a compound to develop further in the advanced and adjuvant therapy of breast cancer.

Taxane–anthracycline combinations in advanced breast cancer
The next phase in the development of taxanes was to combine them with other active agents. Most pivotal trials focused on taxane–anthracyclines combinations for the following reasons:

• Greatest activity as monotherapy.
• Incomplete clinical cross-resistance.
• No overlap of side-effect profiles (with the exception of myelosuppression).

Paclitaxel was first investigated with doxorubicin. While phase II trials reported impressive response rates (42–94%), an unexpectedly high incidence of congestive heart failure (>20%) was observed in some studies, in particular when reaching a cumulative dose of doxorubicin of 360mg/m(2).(10,11)

Further investigations revealed a pharmacokinetic interaction between paclitaxel (when given over 3h) and doxorubicin; paclitaxel decreases hepatic metabolism of the anthracycline and its metabolites, increasing the anthracycline area-under-the-curve (AUC).(12)

Various strategies were therefore developed to prevent cardiotoxicity, such as:

• Limiting the cumulative dose of doxorubicin to 36mg/m(2).
• Increasing the interval between the infusion of the drugs (16h or more).
•  Administering one or both drugs with prolonged infusions.

Paclitaxel–anthracycline combinations
Several randomised trials compared paclitaxel– anthracycline combinations with other programmes in MBC.(5,13–16) In the Intergroup trial previously mentioned, paclitaxel– doxorubicin produced higher response rates (46% vs 33–34%) and time-to-progression (TTP: 8.0 vs 5.9–6.2 months) than either agent alone, but without advantage in overall survival, mostly related to the built-in crossover.(5)

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In another trial comparing 5-FU–doxorubicin–
cyclophosphamide (FAC) with the paclitaxel–doxorubicin doublet, with a 24h-interval between the delivery of paclitaxel and doxorubicin, response rates (68% vs 55%), TTP (8.3 vs 6.2 months) and overall survival (23.3 vs 18.3 months) were superior in the taxane-containing arm.(13) This trial was the first to demonstrate a survival advantage with a taxane–anthracycline combination, although it is noticeable that a small percentage (about 24%) of patients exposed to FAC received subsequent taxane. Additional randomised studies performed by the European Organisation for Research and Treatment of Cancer (EORTC) and a German research team reported similar response rates, TTP and overall survival when paclitaxel–anthracycline was compared with doxorubicin–cyclophosphamide (AC) or epirubicin–cyclophosphamide (EC).(14,15) In the trial conducted by the EORTC, however, doxorubicin dose intensity was decreased in the taxane group due to a high rate of febrile neutropenia and subclinical cardiotoxicity, potentially accounting for the observed lack of difference in efficacy.(14) Finally, a fifth trial performed in the UK compared epirubicin–paclitaxel with EC in 705 patients with MBC.(16) The ET combination yielded higher response rates (67% vs 56%) but no improvement in TTP or overall survival. Taken together, these studies suggest improved response rates and perhaps TTP using paclitaxel–anthracycline combinations, but there is currently no definitive evidence for a significant overall survival advantage.

Docetaxel was also investigated in combination with anthracyclines. In phase I and II trials with doxorubicin or epidoxorubicin, response rates of 57–77% were observed.(17–23) Haematological toxicity was the main issue (neutropenia), with a third of patients developing febrile neutropenia without use of prophylactic growth factors. Importantly, no pharmacokinetic interaction with doxorubucin was reported, and the incidence of cardiac toxicity was no greater than would be expected with doxorubicin alone.(24,25)

Docetaxel–anthracycline combinations
Four randomised trials evaluated docetaxel–anthracycline combinations.(26–30) The first trial (the TAX 306 study) was an international, randomised, phase III trial comparing doxorubicin–docetaxel (AT; 50 and 75mg/m(2), respectively) to standard doxorubicin-cyclophosphamide (AC; 60 and 600mg/m(2), respectively) as first-line therapy in 429 patients with MBC not previously exposed to anthracyclines.(26)

Overall response rates (59% vs 47%; p=0.009) and TTP (37 vs 32 weeks; log-rank p=0.01) were superior in the AT arm. There was no statistically significant difference in overall survival (22.5 vs 21.7 months), most likely due to a high incidence of taxane exposure after failure of AC. The advantage for AT in terms of response was maintained in patients with poor-prognosis features, including the presence of visceral metastases, liver or lung lesions, the involvement of three or more sites or a history of prior adjuvant chemotherapy. The most significant difference between AT and AC in terms of toxicity was the rate of myelosuppression with, respectively, neutropenia Grade 3 and 4 (98% vs 88%), febrile neutropenia (33% vs 10%) and incidence of grade 3/4 infections (8% vs 2%); deaths due to sepsis, however, were not observed in either treatment group. No primary prophylaxis with hematopoietic growth factors was permitted in this trial.

A second international phase III randomised trial (TAX 307) compared docetaxel–doxorubicin- cyclophosphamide (TAC, 50, 75 and 500mg/m(2), respectively) to FAC (500, 50 and 500mg/m(2), respectively) as first-line treatment (prior exposure to anthracyclines allowed) in 484 patients with MBC.  Results in terms of response rates were generally consistent with those observed in the TAX 306 trial. TAC produced higher response rates (55% vs 44%; p=0.02) than FAC. As in the TAX 306 trial, superiority in response rates with TAC was maintained in all subsets of patients with poor-prognosis disease, including those with visceral metastases, more than three organs involved, a history of prior adjuvant chemotherapy (with or without anthracyclines) and a history of prior hormonal therapy for metastatic disease. TTP (7.3 vs 6.7 months) and survival (21 vs 22 months) times did not differ significantly between the two groups.

A third study in a similar patient population compared ET with EC.(29) Response rates (63% vs 34%) and TTP (7.8 vs 5.9 months) were increased in the ET arm. Finally, a fourth small trial was recently carried out, showing superiority of AT versus FAC in terms of response (64% vs 41%), TTP (8.1 vs 6.6 months) and survival (22.6 vs 16.1 months).(30) Overall, these trials consistently show improved response rates and TTP with docetaxel–anthracyline combinations but, thus far, no definitive evidence of a survival advantage has emerged.

Implications of currently available data
A number of comments can be made on the basis of currently available data from the randomised trials comparing taxane–anthracycline combinations with standard anthracycline-containing regimens.

First, response rates are consistently higher in patients receiving taxane–anthracycline combinations than in AC, FAC or EC. In patients with significant disease burden or rapidly progressive visceral disease, in whom immediate disease control is required, the use of a combination regimen, in particular with docetaxel and anthracycline, should be an optimal treatment choice.

Secondly, data regarding TTP are less consistent. Only one of the four trials for paclitaxel combinations and three out of four trials with docetaxel combinations report improved TTP in groups receiving the taxane–anthracycline regimen.  (13,26,29,30)

Thirdly, two trials, one with paclitaxel(13) and the other with docetaxel,(30) have shown a survival advantage secondary to the use of taxane–anthracycline combinations. While there are a number of possible explanations for the lack of survival advantage in the other trials,(14–16,26–29) a probably important cause is related to the high rate of crossover to taxanes in the control groups after disease progression. In the TAX 306 and TAX 307 trials, for example, the rates of crossover to a taxane were 45% and 40%, respectively, and the majority of these patients received docetaxel. These observations are consistent with data presented in the American Intergroup trial,(5) in which doxorubicin, paclitaxel or the combination of both were compared as first-line therapy with built-in crossover when progression on either single-agent arm was observed. Response rates and TTP were improved in the group receiving combination therapy, but overall survival was statistically equivalent in all three treatment arms (20–22 months), confirming no survival advantage in using paclitaxel–doxorubicin in combination versus the sequence of either agent in monochemotherapy. Interestingly, the rate of crossover to taxanes after progression was low in the control group (FAC) of the two trials showing survival advantage, suggesting that the observed survival advantage may have derived from a lack of exposure to taxane after failure of FAC. Overall, the survival results observed with paclitaxel–anthracycline combinations are relatively similar to those reported for docetaxel–anthracycline.

The main question regarding taxane–anthracycline combinations is whether these regimens should be used upfront or whether sequential use of single agents should be employed. Either strategy is reasonable, given the lack of definitive survival advantage with the combinations.

Finally, in terms of toxicity profile and as expected when combining taxanes and anthracyclines, myelosuppression represents the main toxicity, with a high incidence of grade IV neutropenia and febrile neutropenia, in contrast with a low incidence of documented infections and no toxic deaths, as shown in the large-scale, multicentre, randomised trials comparing docetaxel–anthracycline regimens (AT, TAC) to anthracycline polychemotherapies (AC, FAC). It is important to note that none of these studies incorporated any prophylactic use of cytokines (granulocyte colony-stimulating factor [G-CSF]). In a recently published prospective controlled trial investigating the prophylactic use of G-CSF after TAC in patients with advanced breast cancer, the incidence of febrile neutropenia was 6.7%.(31) Documented infections were observed in 1% of patients, and there was no septic death. All these results confirm the feasibility of AT or TAC without prophylactic cytokine support, but also give clinicians an opportunity, when using TAC plus G-CSF, to decrease the risk of neutropenia-induced complications to a level close to what is expected with anthracycline-containing polychemotherapies.

Conclusion
Taxane–anthracycline combinations represent a reasonable first-line option for patients with advanced breast cancer. Overall, it appears that the exposure to a taxane (as opposed to never using a taxane) has the potential to increase the clinical benefit and, in particular, to enhance survival in patients with MBC. However, it is not clear whether upfront combination treatment with anthracycline– taxane combinations is superior to sequential use of single agents. However, there are exceptions to this observation, mostly represented by life-threatening situations in which the use of first-line docetaxel– anthracycline-based regimens could give patients a superior potential for disease control.

Data currently available for advanced disease provide a compelling rationale to develop these combinations further in the adjuvant setting. The first adjuvant results appear promising, with the potential to improve the management of breast cancer and change the natural history of this disease.

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