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Paclitaxel: Epirubicin in metastatic breast cancer – a review
Annals of Oncology 12: 593-598, 2001. © 2001 Kluwer Academic Publishers Printed in the Netherlands.
Review Paclitaxel: Epirubicin in metastatic breast cancer - a review E. D. Razis1 & G. Fountzilas2 '1st Department of Medical Oncology, Hygeia Hospital, Athens; 2AHEPA Hospital, Aristotle University of Thessalomki School of Medicine, Thessalomki, Greece
do not lead to the accumulation of cardiotoxic metabolites as in the case of the doxorubicin-paclitaxel combination. In Background. Treatment of metastatic breast cancer (MBC) terms of efficacy, the ET combination yields an overall rewith paclitaxel (T) and doxorubicin has yielded high response sponse rate of 50%-70% and complete response rate (CR) rates but the regimen is associated with significant cardiac 10%-15% in MBC in the same range as the more recent toxicity. Epirubicin (E) is a less cardiotoxic anthracychne doxorubicin paclitaxel studies. which has also been combined with paclitaxel in the treatment Conclusion. In summary the ET combination is safe and of MBC. effective in MBC. It is less cardiotoxic than the doxorubicinMaterials and methods • This paper is a review of studies paclitaxel combination. Further studies with ET in both the evaluating the pharmacokinetics, toxicity profile, and efficacy adjuvant setting and in MBC are in progress. of the ET combination in MBC. Results: The ET combination has been studied extensively in Europe. The unique pharmacokinetics of the combination Key words: breast cancer, chemotherapy, epirubicin, paclitaxel Summary
Introduction Metastatic breast cancer (MBC) is a largely incurable disease with a highly variable course and a median survival of 16-29 months. It is moderately chemosensitive with some patients achieving responses to first line chemotherapy but also experiencing early relapse, others progressing through all known chemotherapy regimens and yet others maintaining a relatively stable status with sequential chemotherapy regimens for years. Several chemotherapeutic agents have shown single agent activity with overall response rates (ORR) in the range of 10%-40%. In the 70s and 80s, combinations of such agents were tested and found to yield ORR in the range of 40%-60% without significant prolongation of median survival. Meanwhile, retrospective reviews and meta-analyses showed that a very small percentage of complete responders from earlier studies became longterm survivors, yet no regimen had shown an overall survival advantage compared to historical controls. Furthermore, the prevailing theory regarding the advantage of using chemotherapeutic drugs in combination rather than as single agents, was challenged by the NortonSimon hypothesis and its subsequent application in sequential regimens [2]. During the 70s and 80s the single most active agent was considered to be doxorubicin [3]. Paclitaxel (Taxol®) (T) and docetaxel were two new agents that were discovered in the 80s and found to have significant activity in MBC, with single agent ORR between 20% and 40% Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/593/168895 by guest on 27 February 2018
[4]. Because Taxol and anthracyclines exhibit incomplete cross resistance in vitro, the safety and efficacy of their combination was studied in MBC extensively. The combination of doxorubicin and Taxol led to impressively high ORR (60%-90%) in the early studies with complete response (CR) rates of 24%—41% [5, 6], but was associated with significant cardiac and hematologic toxicity. For this reason the correct dosages of the two agents, sequence and schedule of administration of each drug were (and still are) scrutinized. Despite these issues, and because of its activity the combination has become standard first-line therapy in many institutions. In an attempt to maintain efficacy while reducing toxicity, many investigators have combined epirubicin (E) with Taxol [7]. We attempt to review all studies with this combination in MBC.
The agents Taxol is a microtubule stabilizing agent with a unique mechanism of action as a single agent, giving 20%-40% ORR in MBC, even in anthracycline-resistant patients [8]. In the initial studies with this agent in ovarian and breast cancer, the drug was administered at a dose of 135 mg/m 2 as a 24-hour infusion. However, several subsequent studies have shown that three-hour infusions at a dose of 175-250 mg/m 2 are equally effective with improved toxic profile. Epirubicin, a semisynthetic derivative of doxorubicin,
594 causes intercalation of DNA base pairs and Topoisomerase II/DNA complex stabilization, which leads to irreversible DNA strand breakage. Its activity in MBC has been studied extensively. Single agent ORR range between 20% and 40%. It has substituted doxorubicin in several standard combinations such as CAF (cyclophosphamide, doxorubicin (Adriamycin®), fluorouracil) and AC (doxorubicin (Adriamycin®), cyclophosphamide), with ORR up to 54% and median survival 1520 months, and has produced significant ORR as second line chemotherapy in combination with several agents [9]. Pharmacokinetics/pharmacodynamics of the combination Several studies of doxorubicin plus Taxol have shown that the latter increases the plasma concentrations of doxorubicin metabolites and decreases doxorubicin clearance [10]. However, epirubicin has a shorter terminal half-life than doxorubicin and faster clearance. It appears that the administration of Taxol immediately after epirubicin does not affect epirubicin's pharmacokinetic parameters but it does affect its metabolism. This leads to an increase in epidoxorubicinol (EOL) plasma levels, increased levels of its aglycone metabolite 7d-Aone and of EOL glucoronides, i.e. the products of epirubicin' s unique glucuronidation metabolism. This last pathway is particularly important as it results in the production of inactive metabolites and it enhances excretion. Thus, for doxorubicin the parent compound and DOL, an active and cardiotoxic metabolite, are increased by Taxol. On the other hand, in the case of epirubicin, the increased levels of the parent compound and EOL are quickly converted to inactive glucuronides and then quickly excreted. This pathway, which leads to rapid epirubicin elimination, may explain the decreased cardiotoxicity of the combination of Taxol with epirubicin compared to paclitaxel with doxorubicin [11]. When epirubicin is combined with paclitaxel the sequence of drug administration is also significant, as with the doxorubicin/paclitaxel combinations. In combinations where paclitaxel is given before epirubicin (TE), the epirubicin plasma concentration increases, and its terminal half-life decreases, but total plasma exposure to some metabolites decreases. The concentration curves (AUC) are 'qualitatively' different to those seen with the reverse sequence (ET), with peak values seen later and followed by faster clearance [12,13]. These effects result in increased toxicity with TE compared to ET, and the recommended sequence is thus the classic one in which anthracycline is followed by taxane. Moreover, in a study by Conte et al. [14] the levels of epirubicinol dropped with increasing Taxol doses. This is a positive effect, probably caused by the aforementioned effect of Taxol on glucuronidation, i.e., higher doses of Taxol led to increased metabolism of epirubicin Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/593/168895 by guest on 27 February 2018
to EOL, but also induced faster glucuronidation and excretion of EOL. However, this effect is not widely accepted as yet, as it has not been verified by subsequent studies. The taxanes and anthracyclines share certain cellular transport mechanisms. They are both substrates for p-glycoprotein and other proteins involved in drug efflux from tissues. Thus, drug levels in plasma may not fully explain the side effects of the combination. In an animal study where epirubicin was combined with Taxol (and its solvent vehicles), serum and tissue levels of the anthracycline were increased compared to the levels achieved with the anthracycline alone. This increase peaked 24 hours after treatment administration and it was about double that achieved with epirubicin alone. This was true for serum, heart, kidney and liver, but not for lung and spleen [15]. In all studies the pharmacokinetics of Taxol seem unaffected by the co-administration of epirubicin. However, in the study by Conte et al. [14] there seemed to be no correlation between Taxol time at a particular plasma level and myelotoxicity, i.e., a longer time with Taxol plasma levels above the threshold value of 0.05 umol/1, did not correlate with more severe myelosuppression. The authors conclude that Taxol pharmacodynamics may be affected despite the unaffected pharmacokinetics. The toxicity of the combination Both Taxol and the anthracyclines cause myelotoxicity and reversible alopecia. Mucositis is more common with the anthracyclines, whereas neuropathy is quite common with Taxol but is not a side effect of the anthracyclines. Conversely, nausea and vomiting, a common side effect of all anthracyclines, is rare with Taxol. Thus, all patients receiving Taxol with epirubicin will experience grade III alopecia. Other notable non-hematologic toxicity such as nausea and vomiting, arthralgias/ myalgias, asthenia, sensory neuropathy and mucositis, are encountered frequently (up to 100% of cases in some studies) in grades 0-2, but grade 3 or 4 non-hematologic toxicity is seen in less than 2% of cases. Cardiac toxicity will be addressed separately. Hematologic toxicity was the most common treatment side effect in all studies of this combination. With the epirubicin (90 mg/m2) and Taxol (175 mg/m2) combination, 33% of patients experienced grade 1-2 and 67% grade 3-4 leucopenia in the study by Venturini et al. [12]. In two other studies by Luck et al. [16] and Catimel et al. [17] grade 3-4 leucopenia was encountered in 57% of the patients. As mentioned before, in the study by Venturini et al. [12] the reverse sequence (TE) was associated with a higher rate of grade 4 neutropenia (26%). Mean absolute neutrophil count (ANC) nadir was constantly lower with TE than with the more classical ET sequence. Median neutropenia duration was four days in both
595 Table 1 Phase I/II studies with the combination of epirubicin and Taxol in MBC. Author [Reference]
Regimens/ MTD
Lucketal [16]
significant role; these include a history of previous treatment with anthracyclines and chest wall radiotherapy, age, hypertension and diabetes. Patients with these risk factors could develop clinical CHF at lower cumulative epirubicin doses and should be monitored closely [19]. In general, however, the ET combination appears safer than the doxorubicin-Taxol combination as far as cardiac toxicity is concerned.
Line
N (%)
CR (%)
PR (%)
E60 + T225 E90 + TI75
1st
15
12
55
E60 + T200 E50 + T250
1st
>50
-
44
Conteetal [14]
E90 + T200
1st
30
15
65
Phase I—II studies and efficacy/dose (Table 1)
Fountzilas et al [20]
E110 + T225
1st
43
19
36
A few phase I studies of the ET combination have been performed in Europe. In a study with 63 patients, Luck et al. [16] delivered epirubicin over one hour followed by a three-hour infusion of Taxol. The maximum tolerated dose (MTD) of the combination was epirubicin 60 mg/ m 2 with Taxol 225 mg/m 2 , or epirubicin 90 mg/m 2 with Taxol 175 mg/m 2 . In another study [17], including 40 patients, dose-limiting neutropenia and cardiotoxicity were reached at the dose levels of epirubicin 60 mg/m 2 , with Taxol 200 mg/m 2 and epirubicin 50 mg/m 2 with Taxol 250 mg/m 2 , respectively. As mentioned before, Conte et al. published such a study [14], in which 50 patients with MBC received 90 mg/m 2 of epirubicin in combination with escalating doses of Taxol starting at 135 mg/m 2 over three hours. The MTD of Taxol by three-hour infusion given with bolus epirubicin at 90 mg/m 2 , was 200 mg/m 2 . At this dose, 27 patients received six cycles of treatment and experienced febrile neutropenia in 49% of the courses.
Catimeletal. [17]
Abbreviations: MTD - maximum tolerated dose (doses are in mg/m ), N - percentage of patients with previous adjuvant anthracycline based chemotherapy; CR - complete response; PR - partial response; E epirubicin; T - Taxol; 1st - first-line chemotherapy for metastatic disease. Response rates were rounded off.
groups. ANC recovery was slower with TE and thrombocytopenia was more common. With ET, at the aforementioned doses, mild to moderate (grade 1-2) anemia and thrombocytopenia was seen in up to 7% of cases. In our own study with sequential vs. concomitant ET administration toxicity was as in all other phase I—II studies [18].
Cardiac toxicity The most serious complication of the doxorubicin-Taxol combinations has been cardiomyopathy, in some studies occurring in up to 18% of patients [5, 6]. Cardiomyopathy is a known side-effect of the anthracyclines and is directly related to a lifetime cumulative dose of epirubicin of 990 mg/m 2 and doxorubicin 550 mg/m 2 . This is a chronic irreversible cardiomyopathy which leads to congestive heart failure (CHF). In the doxorubicin-Taxol studies it has been found that after a cumulative dose of 480 mg/m 2 of doxorubicin, in combination with 200 mg/m 2 Taxol x 8 cycles, 50% of patients would experience a drop of their left ventricular ejection fraction (LVEF) and 20% would exhibit clinical symptoms of CHF. This percentage is higher than expected with doxorubicin alone and has been attributed to the pharmacokinetics of the combination - i.e. Taxol increases the AUC of doxorubicin by 30%. In all phase I—II studies with ET, myocardial function was monitored. In one study with 17 months follow-up, 18% of patients developed a < 15% decline in LVEF. Four out of 50 patients developed > 15% LVEF decline and three developed mild CHF. Another two patients developed transient hypotension and one died of myocardial infarction on the eleventh day of the first cycle. Overall, in most studies clinical CHF develops in 0%14% of patients at doses lower than 990 mg/m 2 , but in as many as 48% of the patients at doses of 1000 mg/m 2 and more. Baseline cardiac risk factors appear to play a Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/593/168895 by guest on 27 February 2018
All of the phase I — II studies have reported significant response rates. In the study by Conte et al. [14], all patients had MBC and had never received chemotherapy for stage IV disease. The overall response rate was 80% with a 15% CR rate. In this, as in the other studies, a number of patients had received adjuvant chemotherapy, some with anthracycline-containing regimens. In the study by Catimel et al. [17], more than half of the patients had received adjuvant anthracyclines, but none had had chemotherapy for metastatic disease. In a preliminary report of results, partial response (PR) was seen in 44% of patients and stable disease in 48% of patients. In the study by Luck et al. [16], 15% of patients had received anthracycline-containing adjuvant chemotherapy, and all 65 patients had bulky, previously untreated, metastatic disease. The regimen used was epirubicin 60 mg/m 2 given over one hour followed by Taxol 175 mg/ m over three hours for some of the patients or epirubicin 90 mg/m 2 given over one hour followed by Taxol 175 mg/m 2 over three hours in the rest. At the time of the published analysis, 41 patients were evaluable for response with 12% CR for an ORR of 67%. In our own phase II trial [20], 41 patients (previously untreated for MBC) were treated with sequential administration of epirubicin 110 mg/m 2 i.v. bolus every two weeks x 4, followed by Taxol 225 mg/m 2 every two weeks x 4 with G-CSF support, thus administering
596 P = 0.02). Nevertheless, there was no significant difference in ORR between the two groups (55% vs. 42%, P - 0.10). After a median follow-up of 16.5 months, Author (study) [references] Drugs/doses/schedule median TTP was 10 months in group A and 8.5 months Fountzilas (HE 1 lb/97) [18] E80 T175 q3 vs. E110 T225 q2 in group B (P = 0.27). This study failed to demonstrate a suppositional 20% difference in ORR between doseLuck (AGO-BCSG) [29] E60 T175 q3 vs. E60 C600 q3 dense sequential administration of epirubicin and Taxol Carmichael (ABO-1) E75 T200 q3 vs. E75 C600 q3 compared to the combination of the two drugs given on Conte(MIG-6) E90 T200 q3 vs. El20 T250 q3 the same day. Despite the fact that a cost-effectiveness Fountzilas (HE 1 Ob/99) E90 T175 q3 vs. T175 Ca 6 AUC q3 analysis was not performed, it has to be mentioned that Abbreviations: E - epirubicin; T - Taxol, C - cyclophosphamide; Ca G-CSF was prophylactically given to all patients of carboplatin; Doses in mg/m2; q2 - every two weeks, q3 - every three group A and only to 61% of group B. Therefore, the lack weeks. of significant difference in the activity between the two regimens raises serious questions about the cost - effeceach drug at maximal dose and minimizing side effects tiveness of dose-dense sequential chemotherapy, at least [20]. We found that treatment was well tolerated and the in the management of advanced disease. observed ORR was 56% with a 19.5% CR rate, i.e., The second group, coordinated by Dr Conte, is consimilar to that in regimens where the drugs are given ducting a randomized study (MIG-6) in which the comconcomitantly. bination of epirubicin and Taxol is compared to the Overall in these initial studies, the ET combination sequential administration of the two drugs given every appeared to yield lower response rates than those of three weeks. the doxorubicin-Taxol doublet, even though data from There are several other randomized studies, recently randomized studies are lacking. However, it has to be closed to accrual or still ongoing, comparing the epirustated that when the doxorubicin-based combination was bicin/Taxol combination with other regimens. In two studied in phase III, randomized, multi-institutional similar studies, the ABO-1 study (coordinated by Dr studies, it yielded fewer responses than in phase II single Carmichael) and the AGO Breast Cancer Study Group institution trials, probably due to selection bias. There- study (coordinated by Dr Luck) [29], the combination of fore, the two regimens seem indirectly equally effective epirubicin and cyclophosphamide is compared to the in the recent trials, while the ET combination carries a combination of epirubicin and Taxol. The only, albeit significantly lower risk of cardiac toxicity [21-23]. slight, difference between the two studies lies in the dose The optimal duration of therapy with epirubicin and of epirubicin and Taxol. Finally, our group motivated by Taxol as first line chemotherapy in MBC, is still being the significant activity of Taxol and carboplatin in MBC, evaluated. In a multicenter randomized trial (MANTA I), demonstrated in a previous phase II study, [30] is coneight cycles of epirubicin-Taxol followed by eight cycles ducting a randomized study (HE 1 Ob/99) (coordinated of Taxol maintenance are compared to eight cycles of by Dr Fountzilas) comparing the combination of epiruET without maintenance therapy. This latter study was bicin and Taxol with the Taxol-carboplatin doublet. It is based on data from several trials which used mainte- hoped that the mature data of all these studies will nance chemotherapy with CAF or CMF based regi- further elucidate the role of the combination of epirubimens. In another study by Coates et al. [24], prolonged cin and Taxol in the management of MBC. treatment with AC or CMF improved ORR, time to progression (TTP) and quality of life (QOL) compared to shorter treatment with the same regimen. This was New directions confirmed by Muss et al. [25] and Ejlertsen et al. [26] and finalized by a study by ECOG [27]. Thus the Na- The fact that this regimen combined satisfactory efficacy tional Comprehensive Cancer Network recommended with relatively low toxicity encouraged investigators to that MBC patients be treated until progression [28]. combine it with a third drug in an attempt to further improve the results. The most notable of these efforts was with gemcitabine, where the triple combination was used as induction treatment for 36 patients with MBC The randomized studies (Table 2) undergoing high dose therapy (HDT). Patients received Two groups compared the sequential administration of epirubicin 90 mg/m2, Taxol 175 mg/m2 over three hours the two agents to the concomitant use. The Hellenic on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8 Cooperative Oncology Group randomized 183 patients (GET) every three weeks. After six cycles, responding with MBC to either four cycles of epirubicin 110 mg/m2 patients underwent HDT. The GET regimen was well every two weeks x 4 followed by Taxol 225 mg/m2 every tolerated even though grade 4 neutropenia occurred in two weeks with G-CSF support (group A), or six cycles 56% of the patients. The ORR was 89% with a 28% CR of epirubicin 80 mg/m2 followed immediately by Taxol rate. After HDT, the ORR was raised to 92% with 44% 175 mg/m2 over three hours every three weeks (group B) CR rate. Further studies with this combination are [18]. The CR rate was higher in group A (21.5% vs. 9%, planned [31]. Table 2. Randomized studies with the combination of epirubicin and Taxol in MBC
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597 Other triplets, combining Taxol and epirubicin with cisplatin, cyclophosphamide and navelbine are being tested. The efficacy and tolerability of the ET combination has also led to adjuvant studies with this regimen. The addition of Taxol to the adjuvant therapy of node positive, early breast cancer was shown to improve survival compared to standard AC treatment in an intergroup study in the US [32]. Several confirmatory European studies are using epirubicin instead of doxorubicin because long-term toxicity, including cardiotoxicity, is of paramount importance in the adjuvant setting, where patients are expected to survive longer than those with MBC. These studies compare a standard regimen such as FEC, EC or CMF to the same regimen plus Taxol or to the ET combination.
5
6.
7. 8.
9.
10.
11.
Conclusions Epirubicin and Taxol is a safe and effective combination as first line chemotherapy of MBC. The optimal drug doses of the combination are 60-90 mg/m 2 of epirubicin i.v. bolus followed by 175-200 mg/m 2 of Taxol as a three-hour infusion, every 21 days for 6-8 cycles in patients with normal LVEF In these doses, alopecia, leucopenia and neutropenia are the most significant side effects, while peripheral neuropathy, nausea, vomiting and mucositis are frequently encountered, though only in mild degrees. Though a drop in LVEF is common, clinical CHF in the absence of other risk factors is rare in these dosages. Clinical efficacy is relatively satisfactory with ORR in the range of 50%-70% with approximately 10%-15% CR rate, even in patients who have received adjuvant anthracycline-based therapy. Even though no randomized studies comparing the doxorubicin-Taxol combination with ETare published in the literature, there are sufficient data suggesting that these combinations are equally effective in MBC. Moreover, the reduced cardiotoxicity of ET makes it an attractive alternative to the combination of doxorubicin and Taxol. For these reasons, the ET combination is currently being evaluated in randomized studies in the adjuvant setting as well as in MBC.
12
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16.
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Correspondence to: E. D. Razis, MD 1st Deparment of Medical Oncology Hygeia Hospital 4 Er. Stavrou & Kifissias Ave Maroussi, Athens 151-23 Greece E-mail: [email protected]
Review Paclitaxel: Epirubicin in metastatic breast cancer - a review E. D. Razis1 & G. Fountzilas2 '1st Department of Medical Oncology, Hygeia Hospital, Athens; 2AHEPA Hospital, Aristotle University of Thessalomki School of Medicine, Thessalomki, Greece
do not lead to the accumulation of cardiotoxic metabolites as in the case of the doxorubicin-paclitaxel combination. In Background. Treatment of metastatic breast cancer (MBC) terms of efficacy, the ET combination yields an overall rewith paclitaxel (T) and doxorubicin has yielded high response sponse rate of 50%-70% and complete response rate (CR) rates but the regimen is associated with significant cardiac 10%-15% in MBC in the same range as the more recent toxicity. Epirubicin (E) is a less cardiotoxic anthracychne doxorubicin paclitaxel studies. which has also been combined with paclitaxel in the treatment Conclusion. In summary the ET combination is safe and of MBC. effective in MBC. It is less cardiotoxic than the doxorubicinMaterials and methods • This paper is a review of studies paclitaxel combination. Further studies with ET in both the evaluating the pharmacokinetics, toxicity profile, and efficacy adjuvant setting and in MBC are in progress. of the ET combination in MBC. Results: The ET combination has been studied extensively in Europe. The unique pharmacokinetics of the combination Key words: breast cancer, chemotherapy, epirubicin, paclitaxel Summary
Introduction Metastatic breast cancer (MBC) is a largely incurable disease with a highly variable course and a median survival of 16-29 months. It is moderately chemosensitive with some patients achieving responses to first line chemotherapy but also experiencing early relapse, others progressing through all known chemotherapy regimens and yet others maintaining a relatively stable status with sequential chemotherapy regimens for years. Several chemotherapeutic agents have shown single agent activity with overall response rates (ORR) in the range of 10%-40%. In the 70s and 80s, combinations of such agents were tested and found to yield ORR in the range of 40%-60% without significant prolongation of median survival. Meanwhile, retrospective reviews and meta-analyses showed that a very small percentage of complete responders from earlier studies became longterm survivors, yet no regimen had shown an overall survival advantage compared to historical controls. Furthermore, the prevailing theory regarding the advantage of using chemotherapeutic drugs in combination rather than as single agents, was challenged by the NortonSimon hypothesis and its subsequent application in sequential regimens [2]. During the 70s and 80s the single most active agent was considered to be doxorubicin [3]. Paclitaxel (Taxol®) (T) and docetaxel were two new agents that were discovered in the 80s and found to have significant activity in MBC, with single agent ORR between 20% and 40% Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/593/168895 by guest on 27 February 2018
[4]. Because Taxol and anthracyclines exhibit incomplete cross resistance in vitro, the safety and efficacy of their combination was studied in MBC extensively. The combination of doxorubicin and Taxol led to impressively high ORR (60%-90%) in the early studies with complete response (CR) rates of 24%—41% [5, 6], but was associated with significant cardiac and hematologic toxicity. For this reason the correct dosages of the two agents, sequence and schedule of administration of each drug were (and still are) scrutinized. Despite these issues, and because of its activity the combination has become standard first-line therapy in many institutions. In an attempt to maintain efficacy while reducing toxicity, many investigators have combined epirubicin (E) with Taxol [7]. We attempt to review all studies with this combination in MBC.
The agents Taxol is a microtubule stabilizing agent with a unique mechanism of action as a single agent, giving 20%-40% ORR in MBC, even in anthracycline-resistant patients [8]. In the initial studies with this agent in ovarian and breast cancer, the drug was administered at a dose of 135 mg/m 2 as a 24-hour infusion. However, several subsequent studies have shown that three-hour infusions at a dose of 175-250 mg/m 2 are equally effective with improved toxic profile. Epirubicin, a semisynthetic derivative of doxorubicin,
594 causes intercalation of DNA base pairs and Topoisomerase II/DNA complex stabilization, which leads to irreversible DNA strand breakage. Its activity in MBC has been studied extensively. Single agent ORR range between 20% and 40%. It has substituted doxorubicin in several standard combinations such as CAF (cyclophosphamide, doxorubicin (Adriamycin®), fluorouracil) and AC (doxorubicin (Adriamycin®), cyclophosphamide), with ORR up to 54% and median survival 1520 months, and has produced significant ORR as second line chemotherapy in combination with several agents [9]. Pharmacokinetics/pharmacodynamics of the combination Several studies of doxorubicin plus Taxol have shown that the latter increases the plasma concentrations of doxorubicin metabolites and decreases doxorubicin clearance [10]. However, epirubicin has a shorter terminal half-life than doxorubicin and faster clearance. It appears that the administration of Taxol immediately after epirubicin does not affect epirubicin's pharmacokinetic parameters but it does affect its metabolism. This leads to an increase in epidoxorubicinol (EOL) plasma levels, increased levels of its aglycone metabolite 7d-Aone and of EOL glucoronides, i.e. the products of epirubicin' s unique glucuronidation metabolism. This last pathway is particularly important as it results in the production of inactive metabolites and it enhances excretion. Thus, for doxorubicin the parent compound and DOL, an active and cardiotoxic metabolite, are increased by Taxol. On the other hand, in the case of epirubicin, the increased levels of the parent compound and EOL are quickly converted to inactive glucuronides and then quickly excreted. This pathway, which leads to rapid epirubicin elimination, may explain the decreased cardiotoxicity of the combination of Taxol with epirubicin compared to paclitaxel with doxorubicin [11]. When epirubicin is combined with paclitaxel the sequence of drug administration is also significant, as with the doxorubicin/paclitaxel combinations. In combinations where paclitaxel is given before epirubicin (TE), the epirubicin plasma concentration increases, and its terminal half-life decreases, but total plasma exposure to some metabolites decreases. The concentration curves (AUC) are 'qualitatively' different to those seen with the reverse sequence (ET), with peak values seen later and followed by faster clearance [12,13]. These effects result in increased toxicity with TE compared to ET, and the recommended sequence is thus the classic one in which anthracycline is followed by taxane. Moreover, in a study by Conte et al. [14] the levels of epirubicinol dropped with increasing Taxol doses. This is a positive effect, probably caused by the aforementioned effect of Taxol on glucuronidation, i.e., higher doses of Taxol led to increased metabolism of epirubicin Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/593/168895 by guest on 27 February 2018
to EOL, but also induced faster glucuronidation and excretion of EOL. However, this effect is not widely accepted as yet, as it has not been verified by subsequent studies. The taxanes and anthracyclines share certain cellular transport mechanisms. They are both substrates for p-glycoprotein and other proteins involved in drug efflux from tissues. Thus, drug levels in plasma may not fully explain the side effects of the combination. In an animal study where epirubicin was combined with Taxol (and its solvent vehicles), serum and tissue levels of the anthracycline were increased compared to the levels achieved with the anthracycline alone. This increase peaked 24 hours after treatment administration and it was about double that achieved with epirubicin alone. This was true for serum, heart, kidney and liver, but not for lung and spleen [15]. In all studies the pharmacokinetics of Taxol seem unaffected by the co-administration of epirubicin. However, in the study by Conte et al. [14] there seemed to be no correlation between Taxol time at a particular plasma level and myelotoxicity, i.e., a longer time with Taxol plasma levels above the threshold value of 0.05 umol/1, did not correlate with more severe myelosuppression. The authors conclude that Taxol pharmacodynamics may be affected despite the unaffected pharmacokinetics. The toxicity of the combination Both Taxol and the anthracyclines cause myelotoxicity and reversible alopecia. Mucositis is more common with the anthracyclines, whereas neuropathy is quite common with Taxol but is not a side effect of the anthracyclines. Conversely, nausea and vomiting, a common side effect of all anthracyclines, is rare with Taxol. Thus, all patients receiving Taxol with epirubicin will experience grade III alopecia. Other notable non-hematologic toxicity such as nausea and vomiting, arthralgias/ myalgias, asthenia, sensory neuropathy and mucositis, are encountered frequently (up to 100% of cases in some studies) in grades 0-2, but grade 3 or 4 non-hematologic toxicity is seen in less than 2% of cases. Cardiac toxicity will be addressed separately. Hematologic toxicity was the most common treatment side effect in all studies of this combination. With the epirubicin (90 mg/m2) and Taxol (175 mg/m2) combination, 33% of patients experienced grade 1-2 and 67% grade 3-4 leucopenia in the study by Venturini et al. [12]. In two other studies by Luck et al. [16] and Catimel et al. [17] grade 3-4 leucopenia was encountered in 57% of the patients. As mentioned before, in the study by Venturini et al. [12] the reverse sequence (TE) was associated with a higher rate of grade 4 neutropenia (26%). Mean absolute neutrophil count (ANC) nadir was constantly lower with TE than with the more classical ET sequence. Median neutropenia duration was four days in both
595 Table 1 Phase I/II studies with the combination of epirubicin and Taxol in MBC. Author [Reference]
Regimens/ MTD
Lucketal [16]
significant role; these include a history of previous treatment with anthracyclines and chest wall radiotherapy, age, hypertension and diabetes. Patients with these risk factors could develop clinical CHF at lower cumulative epirubicin doses and should be monitored closely [19]. In general, however, the ET combination appears safer than the doxorubicin-Taxol combination as far as cardiac toxicity is concerned.
Line
N (%)
CR (%)
PR (%)
E60 + T225 E90 + TI75
1st
15
12
55
E60 + T200 E50 + T250
1st
>50
-
44
Conteetal [14]
E90 + T200
1st
30
15
65
Phase I—II studies and efficacy/dose (Table 1)
Fountzilas et al [20]
E110 + T225
1st
43
19
36
A few phase I studies of the ET combination have been performed in Europe. In a study with 63 patients, Luck et al. [16] delivered epirubicin over one hour followed by a three-hour infusion of Taxol. The maximum tolerated dose (MTD) of the combination was epirubicin 60 mg/ m 2 with Taxol 225 mg/m 2 , or epirubicin 90 mg/m 2 with Taxol 175 mg/m 2 . In another study [17], including 40 patients, dose-limiting neutropenia and cardiotoxicity were reached at the dose levels of epirubicin 60 mg/m 2 , with Taxol 200 mg/m 2 and epirubicin 50 mg/m 2 with Taxol 250 mg/m 2 , respectively. As mentioned before, Conte et al. published such a study [14], in which 50 patients with MBC received 90 mg/m 2 of epirubicin in combination with escalating doses of Taxol starting at 135 mg/m 2 over three hours. The MTD of Taxol by three-hour infusion given with bolus epirubicin at 90 mg/m 2 , was 200 mg/m 2 . At this dose, 27 patients received six cycles of treatment and experienced febrile neutropenia in 49% of the courses.
Catimeletal. [17]
Abbreviations: MTD - maximum tolerated dose (doses are in mg/m ), N - percentage of patients with previous adjuvant anthracycline based chemotherapy; CR - complete response; PR - partial response; E epirubicin; T - Taxol; 1st - first-line chemotherapy for metastatic disease. Response rates were rounded off.
groups. ANC recovery was slower with TE and thrombocytopenia was more common. With ET, at the aforementioned doses, mild to moderate (grade 1-2) anemia and thrombocytopenia was seen in up to 7% of cases. In our own study with sequential vs. concomitant ET administration toxicity was as in all other phase I—II studies [18].
Cardiac toxicity The most serious complication of the doxorubicin-Taxol combinations has been cardiomyopathy, in some studies occurring in up to 18% of patients [5, 6]. Cardiomyopathy is a known side-effect of the anthracyclines and is directly related to a lifetime cumulative dose of epirubicin of 990 mg/m 2 and doxorubicin 550 mg/m 2 . This is a chronic irreversible cardiomyopathy which leads to congestive heart failure (CHF). In the doxorubicin-Taxol studies it has been found that after a cumulative dose of 480 mg/m 2 of doxorubicin, in combination with 200 mg/m 2 Taxol x 8 cycles, 50% of patients would experience a drop of their left ventricular ejection fraction (LVEF) and 20% would exhibit clinical symptoms of CHF. This percentage is higher than expected with doxorubicin alone and has been attributed to the pharmacokinetics of the combination - i.e. Taxol increases the AUC of doxorubicin by 30%. In all phase I—II studies with ET, myocardial function was monitored. In one study with 17 months follow-up, 18% of patients developed a < 15% decline in LVEF. Four out of 50 patients developed > 15% LVEF decline and three developed mild CHF. Another two patients developed transient hypotension and one died of myocardial infarction on the eleventh day of the first cycle. Overall, in most studies clinical CHF develops in 0%14% of patients at doses lower than 990 mg/m 2 , but in as many as 48% of the patients at doses of 1000 mg/m 2 and more. Baseline cardiac risk factors appear to play a Downloaded from https://academic.oup.com/annonc/article-abstract/12/5/593/168895 by guest on 27 February 2018
All of the phase I — II studies have reported significant response rates. In the study by Conte et al. [14], all patients had MBC and had never received chemotherapy for stage IV disease. The overall response rate was 80% with a 15% CR rate. In this, as in the other studies, a number of patients had received adjuvant chemotherapy, some with anthracycline-containing regimens. In the study by Catimel et al. [17], more than half of the patients had received adjuvant anthracyclines, but none had had chemotherapy for metastatic disease. In a preliminary report of results, partial response (PR) was seen in 44% of patients and stable disease in 48% of patients. In the study by Luck et al. [16], 15% of patients had received anthracycline-containing adjuvant chemotherapy, and all 65 patients had bulky, previously untreated, metastatic disease. The regimen used was epirubicin 60 mg/m 2 given over one hour followed by Taxol 175 mg/ m over three hours for some of the patients or epirubicin 90 mg/m 2 given over one hour followed by Taxol 175 mg/m 2 over three hours in the rest. At the time of the published analysis, 41 patients were evaluable for response with 12% CR for an ORR of 67%. In our own phase II trial [20], 41 patients (previously untreated for MBC) were treated with sequential administration of epirubicin 110 mg/m 2 i.v. bolus every two weeks x 4, followed by Taxol 225 mg/m 2 every two weeks x 4 with G-CSF support, thus administering
596 P = 0.02). Nevertheless, there was no significant difference in ORR between the two groups (55% vs. 42%, P - 0.10). After a median follow-up of 16.5 months, Author (study) [references] Drugs/doses/schedule median TTP was 10 months in group A and 8.5 months Fountzilas (HE 1 lb/97) [18] E80 T175 q3 vs. E110 T225 q2 in group B (P = 0.27). This study failed to demonstrate a suppositional 20% difference in ORR between doseLuck (AGO-BCSG) [29] E60 T175 q3 vs. E60 C600 q3 dense sequential administration of epirubicin and Taxol Carmichael (ABO-1) E75 T200 q3 vs. E75 C600 q3 compared to the combination of the two drugs given on Conte(MIG-6) E90 T200 q3 vs. El20 T250 q3 the same day. Despite the fact that a cost-effectiveness Fountzilas (HE 1 Ob/99) E90 T175 q3 vs. T175 Ca 6 AUC q3 analysis was not performed, it has to be mentioned that Abbreviations: E - epirubicin; T - Taxol, C - cyclophosphamide; Ca G-CSF was prophylactically given to all patients of carboplatin; Doses in mg/m2; q2 - every two weeks, q3 - every three group A and only to 61% of group B. Therefore, the lack weeks. of significant difference in the activity between the two regimens raises serious questions about the cost - effeceach drug at maximal dose and minimizing side effects tiveness of dose-dense sequential chemotherapy, at least [20]. We found that treatment was well tolerated and the in the management of advanced disease. observed ORR was 56% with a 19.5% CR rate, i.e., The second group, coordinated by Dr Conte, is consimilar to that in regimens where the drugs are given ducting a randomized study (MIG-6) in which the comconcomitantly. bination of epirubicin and Taxol is compared to the Overall in these initial studies, the ET combination sequential administration of the two drugs given every appeared to yield lower response rates than those of three weeks. the doxorubicin-Taxol doublet, even though data from There are several other randomized studies, recently randomized studies are lacking. However, it has to be closed to accrual or still ongoing, comparing the epirustated that when the doxorubicin-based combination was bicin/Taxol combination with other regimens. In two studied in phase III, randomized, multi-institutional similar studies, the ABO-1 study (coordinated by Dr studies, it yielded fewer responses than in phase II single Carmichael) and the AGO Breast Cancer Study Group institution trials, probably due to selection bias. There- study (coordinated by Dr Luck) [29], the combination of fore, the two regimens seem indirectly equally effective epirubicin and cyclophosphamide is compared to the in the recent trials, while the ET combination carries a combination of epirubicin and Taxol. The only, albeit significantly lower risk of cardiac toxicity [21-23]. slight, difference between the two studies lies in the dose The optimal duration of therapy with epirubicin and of epirubicin and Taxol. Finally, our group motivated by Taxol as first line chemotherapy in MBC, is still being the significant activity of Taxol and carboplatin in MBC, evaluated. In a multicenter randomized trial (MANTA I), demonstrated in a previous phase II study, [30] is coneight cycles of epirubicin-Taxol followed by eight cycles ducting a randomized study (HE 1 Ob/99) (coordinated of Taxol maintenance are compared to eight cycles of by Dr Fountzilas) comparing the combination of epiruET without maintenance therapy. This latter study was bicin and Taxol with the Taxol-carboplatin doublet. It is based on data from several trials which used mainte- hoped that the mature data of all these studies will nance chemotherapy with CAF or CMF based regi- further elucidate the role of the combination of epirubimens. In another study by Coates et al. [24], prolonged cin and Taxol in the management of MBC. treatment with AC or CMF improved ORR, time to progression (TTP) and quality of life (QOL) compared to shorter treatment with the same regimen. This was New directions confirmed by Muss et al. [25] and Ejlertsen et al. [26] and finalized by a study by ECOG [27]. Thus the Na- The fact that this regimen combined satisfactory efficacy tional Comprehensive Cancer Network recommended with relatively low toxicity encouraged investigators to that MBC patients be treated until progression [28]. combine it with a third drug in an attempt to further improve the results. The most notable of these efforts was with gemcitabine, where the triple combination was used as induction treatment for 36 patients with MBC The randomized studies (Table 2) undergoing high dose therapy (HDT). Patients received Two groups compared the sequential administration of epirubicin 90 mg/m2, Taxol 175 mg/m2 over three hours the two agents to the concomitant use. The Hellenic on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8 Cooperative Oncology Group randomized 183 patients (GET) every three weeks. After six cycles, responding with MBC to either four cycles of epirubicin 110 mg/m2 patients underwent HDT. The GET regimen was well every two weeks x 4 followed by Taxol 225 mg/m2 every tolerated even though grade 4 neutropenia occurred in two weeks with G-CSF support (group A), or six cycles 56% of the patients. The ORR was 89% with a 28% CR of epirubicin 80 mg/m2 followed immediately by Taxol rate. After HDT, the ORR was raised to 92% with 44% 175 mg/m2 over three hours every three weeks (group B) CR rate. Further studies with this combination are [18]. The CR rate was higher in group A (21.5% vs. 9%, planned [31]. Table 2. Randomized studies with the combination of epirubicin and Taxol in MBC
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597 Other triplets, combining Taxol and epirubicin with cisplatin, cyclophosphamide and navelbine are being tested. The efficacy and tolerability of the ET combination has also led to adjuvant studies with this regimen. The addition of Taxol to the adjuvant therapy of node positive, early breast cancer was shown to improve survival compared to standard AC treatment in an intergroup study in the US [32]. Several confirmatory European studies are using epirubicin instead of doxorubicin because long-term toxicity, including cardiotoxicity, is of paramount importance in the adjuvant setting, where patients are expected to survive longer than those with MBC. These studies compare a standard regimen such as FEC, EC or CMF to the same regimen plus Taxol or to the ET combination.
5
6.
7. 8.
9.
10.
11.
Conclusions Epirubicin and Taxol is a safe and effective combination as first line chemotherapy of MBC. The optimal drug doses of the combination are 60-90 mg/m 2 of epirubicin i.v. bolus followed by 175-200 mg/m 2 of Taxol as a three-hour infusion, every 21 days for 6-8 cycles in patients with normal LVEF In these doses, alopecia, leucopenia and neutropenia are the most significant side effects, while peripheral neuropathy, nausea, vomiting and mucositis are frequently encountered, though only in mild degrees. Though a drop in LVEF is common, clinical CHF in the absence of other risk factors is rare in these dosages. Clinical efficacy is relatively satisfactory with ORR in the range of 50%-70% with approximately 10%-15% CR rate, even in patients who have received adjuvant anthracycline-based therapy. Even though no randomized studies comparing the doxorubicin-Taxol combination with ETare published in the literature, there are sufficient data suggesting that these combinations are equally effective in MBC. Moreover, the reduced cardiotoxicity of ET makes it an attractive alternative to the combination of doxorubicin and Taxol. For these reasons, the ET combination is currently being evaluated in randomized studies in the adjuvant setting as well as in MBC.
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Correspondence to: E. D. Razis, MD 1st Deparment of Medical Oncology Hygeia Hospital 4 Er. Stavrou & Kifissias Ave Maroussi, Athens 151-23 Greece E-mail: [email protected]