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Anthracyclines-paclitaxel combinations in the treatment of breast cancer
Annals of Oncology 8: 939-943, 1997. © 1997 Kluwtr Academic Publishers. Primed in the Netherlands.
Review Anthracyclines-paclitaxel combinations in the treatment of breast cancer P. F. Conte & A. Gennari Department of Oncology, Division of Medical Oncology, St. Chiara Hospital, Pisa, Italy
Key words: breast cancer, Taxol-anthracycline combination
Introduction
The incorporation of anthracyclines in combination regimens has increased the response rates, remission duration and survival of patients with advanced breast cancer [1], with approximately 20% of the patients still disease-free 10 years after achievement of complete response [2]. Moreover, at least in some trials, in patients with early breast cancer anthracycline-based adjuvant chemotherapy has produced better relapse-free survival and survival than CMF or tamoxifen [3-7]. These data indicate that the prognosis of early and advanced breast cancer can be improved by incorporating the more active drugs in combination regimens. On these premises the activity of paclitaxel has evoked considerable interest: as a single agent it has produced a response rate higher than 50% in chemonaive patients [8] and as high as 20%-30% in patients previously treated with anthracyclines [9, 10]. Doxorubicin-paclitaxel combinations Because of its high level of activity and non-complete cross-resistance, several trials have been performed to evaluate the feasibility and toxic effects of doxorubicin combined with paclitaxel. The early phase I—II studies used paclitaxel by prolonged infusion (24 or 72 hours) with doxorubicin given concomitantly for 72 hours [11], by 48-hour infusion immediately before or after paclitaxel [12] or as an i.v. bolus four hours before or after paclitaxel [13]. With these regimens the dose-limiting toxicities (mucositis, febrile neutropenia, typhlitis) appear at relatively low doses and are schedule-dependent, with doxorubicin followed by paclitaxel being less toxic. Moreover, the overall and complete response rates were lower than expected, suggesting that the cytotoxicity of this combination is subcumulative. Subsequent to these trials, preclinical studies have shown conflicting data on the interactions between doxorubicin and paclitaxel in vitro, with some studies demonstrating sub-cumulative cytotoxicity and
others sequence-dependent synergy [14-17]. Apart from possible cytotoxic interactions, other factors may contribute to the suboptimal activity of this regimen: the non-linear pharmacokinetics of paclitaxel [18], the presence of Cremophor EL which might alter the cytotoxicity of the taxane and the intracellular concentration of anthracycline [19, 20] and the alteration of doxorubicin pharmacokinetics induced by prior or concomitant paclitaxel [12, 21, 22]. Following the demonstration of the safety and activity of paclitaxel given as short infusions [23, 24], European investigators have performed trials using bolus doxorubicin and paclitaxel over three hours. The most relevant findings of these studies were: the lack of sequence-dependent toxicity [25], the high incidence of symptomatic CHF [25, 26] and the striking antitumor activity, with a response rate in the range of 90% and a complete remission rate as high as 24%—41% [25—27]. The antitumor activity and the cardiac effects of this combination suggested the possibility of a therapeutic and toxic enhancement between the two drugs. As for cardiotoxicity, in two studies [25, 26] 13 of 64 patients (20%) developed a CHF; seven of these patients had personal risk factors for cardiopathic disease but only one died because of cardiomyopathy. The cardiotoxic events occurred at median cumulative doxorubicin doses of 392-480 mg/sqm, well below the maximum recommended cumulative doses of 550 mg/sqm [28, 29]. On the basis of these results the maximum cumulative dose of bolus doxorubicin in combination with paclitaxel over three hours should not exceed 360 mg/sqm. The enhanced cardiotoxicity of this combination can be explained by the reduced elimination of doxorubicinol induced by paclitaxel at the hepatic level [30]. It is of interest that when doxorubicin was given 16 hours before paclitaxel no cardiotoxic events occurred [27]; this interval of administration corresponds to the initial and intermediate half-lives of doxorubicin and doxorubicinol [31, 32] Ongoing trials will clarify whether a time interval between administrations of doxorubicin and paclitaxel is necessary and if so, how long it should be, for main-
940 tenance of cytotoxicity and restriction of cardiotoxicity (Table 1). Epirubicin-paclitaxel combinations Apart from schedule-optimization and lower cumulative doses of doxorubicin, the cardiotoxicity of the anthracycline-taxane combination might be reduced by employing a less cardiotoxic analog. Epirubicin seems particularly attractive because of its antitumor activity, which is similar to that of the parent compound, with reduced cardiotoxicity and mucositis [33]. The dose-finding studies of the epirubicin-paclitaxel combination were started when the preliminary data of doxorubicin-paclitaxel were already available, so the investigators administered the taxane as a short infusion and the patients were carefully monitored for potential cardiotoxicity. Some of these studies have been completed and the most striking feature is the lack of cardiac toxicity: only 6% of the patients showed a decline of the left ventricular ejection fraction below 50% and developed a mild congestive heart failure; in particular, only three of our patients experienced a grade 3 cardiotoxicity, the first two at cumulative epirubicin doses of 720 and 1080 mg/sqm, and the third after 540 mg/sqm cumulative epirubicin followed by high-dose chemotherapy [34-37]. The excellent cardiac tolerability of this combination cannot be explained solely on the basis of the lower cardiotoxic effects of epirubicin. Additional explanations could be a better selection of the patients and, at least in two trials [35, 36], the use of low epirubicin doses. However, very recent studies from Gianni et al. [30] and our group [37] have shown that the co-administration of epirubicin and paclitaxel induces an increased glucurunidation of epirubicin, leading to increased urinary elimination and decreased plasma levels of epirubicinol; these secondary alcohol metabolites (doxorubicinol and epirubicinol) have been shown to play an important role in the pathogenesis of cardiac damage [38]. Therefore, the pharmacokinetic interferences of anthracycline-paclitaxel are completely different according to the anthracycline employed, with the doxorubicin-paclitaxel combination showing a potentiation of cardiotoxicity that is not observed with the epirubicin-paclitaxel combinations. The logical question then is: do these pharmacokinetic interferences alter the antitumor activity of the combination? In two trials the overall and the complete response rates were 44%-50% and less than 10%, respectively [35, 36]; in our trial the overall response rate was 84% but the rate of complete remissions was 19% only [37]. These response rates and particularly that of the complete responses are lower than those reported with the doxorubicin-paclitaxel regimens; however, there are profound differences in the characteristics of the patients and in the anthracycline dosages across these studies.
Table 1. Anthracyclines-paclitaxel as first-line therapy in advanced breast cancer: ongoing randomized trials. Study group
Study design
EORTC SWOG Eastern Europe NL, Germany GONO ECOG
A 60 + P 175 vs. A 60 + C 600 A 60 + P 200 vs. A 60 + C 750 A 50 -> 24 hrs - P 220 vs. FAC (500/50/500) A 60 + P 200 vs. E 90 + P 200 E 90 + P 200 vs. E 120 x 4 - . P 250 x 4 P -• A vs. A -• Pvs. A + P
Abbreviations: A - doxorubicin; P - paclitaxel (over 3 hrs); F - 5-FU; C - cyclophosphamide; E - epirubicin. All doses are mg/sqm.
In the doxorubicin-paclitaxel trials 72% of the patients were chemo-naive and most of them had never received any kind of endocrine therapy; by contrast, in the epirubicin-paclitaxel studies 60% of the patients had failed adjuvant chemotherapy which in some cases included anthracyclines, and a significant number of them were pretreated with hormonal therapy for advanced disease. A multivariate analysis has recently demonstrated that these pretreatments have a significant impact on the probability of response [39]. Moreover, in two studies the majority of the patients were treated with epirubicin doses of 50 to 60 mg/sqm [35, 36]. Several randomized trials in early and advanced breast cancer have demonstrated for epirubicin a significant dose-effect relationship up to doses of 90-100 mg/sqm [40-44]. In contrast, in the doxorubicin trials the dose of anthracycline was 60 mg/sqm, which corresponds to the 90 mg/sqm of epirubicin we used in our study. Apart from the patients' characteristics and the dose issue, other data must be analysed to determine whether the co-administration of epirubicin and paclitaxel modifies the cytotoxicity of the two drugs. The pharmacokinetic of paclitaxel when given as a single agent is nonlinear and its pharmacodynamic effects, particularly neutropenia, are non-linearly related to the time that paclitaxel spends above the threshold plasma concentration of 0.05 urn [45]. On the other hand, in our study the severity and duration of neutropenia were not significantly related to the administered dose of paclitaxel or to the time spent above the threshold plasma concentration [37]. Together the pharmacokinetic data and the pharmacodynamic effects indicate that the co-administration of epirubicin with paclitaxel does not compromise the cardiac tolerability of the anthracycline and modifies the relationship between paclitaxel plasma concentration and neutropenia. Therefore, we cannot exclude the possibility that the combination of the two drugs results in sub-additive antitumor activity. To clarify this point, we are presently conducting a randomized trial comparing eight courses of epirubicinpaclitaxel given in combination to four courses of fulldose epirubicin (120 mg/sqm) followed by four courses of paclitaxel (250 mg/sqm over three hours) (Table 1).
941 Even if the question of the 'best schedule' is still open, these studies demonstrate that an anthracycline plus paclitaxel is probabily the most active regimen available in the treatment of advanced breast cancer. Role of anthracycline-paclitaxel in the management of advanced breast cancer ~~ ~ ~~ Outside clinical trials, the biological and economic costs of these regimens must be taken into account when defining their role in the management of breast cancer. Up to now in advanced breast cancer chemotherapy has been mainly given for palliation in patients with hormone-resistant and rapidly progressive visceral disease. However, two recently published papers have reported that approximatively 20% of women with metastatic breast cancer who have achieved a clinical complete remission with standard-dose chemotherapy have survived free of disease for more than five years [2, 46]. Worthy of note is the fact that such prolonged disease-free survivals have never been observed with non-anthracycline-based regimens [47, 48]. Will the complete remissions obtained with anthracycline-paclitaxel be as durable as those achieved with other anthracyclin-based regimens? If so, we should really 'dream the impossible dream' of treating some patients with curative intent [49]. Such a dream could transmute into reality if the role of high-dose chemotherapy with hemopoietic stem cell support is confirmed by ongoing randomized trials. In this setting the epirubicin-paclitaxel combination is of particular interest; in fact this regimen is very effective in mobilizing peripheral blood progenitors [50], and patients can be treated with 6 courses of induction epirubicin-paclitaxel followed by a myeloablative course of thiotepa-melphalan with good cardiac tolerance.
Table 2 Anthracyclines-taxanes as adjuvant chemotherapy: ongoing randomized trials. Study group
Study design
CALGB ECTO (INT Milan)
A (60 vs. 75 vs. 90) C x 4 ± P x 4 Surgery + A x 4 + CMF x 4 vs. Surgery + AP * 4T- C M F M vs. AP x 4 + CMF x 4 + surgery AC x 4 ± P x 4 EP x 4 vs. CEF x 6 E x 6 vs. E x 3 + D x 3
--
—
-
-
-
NSABP GONO ICCG
Abbreviations. A - doxorubicin; P - paclitaxel (over 3 hrs); F - 5-FU; C - cyclophosphamide; E - epirubicin; D - docetaxel; M - methotrexate.
docetaxel combination also appear very promising [53]. 2) the short infusion of paclitaxel is the preferred one in combination; 3) the short infusion of paclitaxel is still associated with altered pharmacokinetics of doxorubicin and epirubicin that is different for the two drugs. These pharmacokinetic differences may be relevant both in terms of cardiotoxicity and activity; 4) the pharmacokinetic interactions between paclitaxel and other drugs should be considered before planning clinical trials. Acknowledgement Supported in part by a grant from AIRC (Associazione Italiana Ricerca Cancro). References
Future developments In spite of the uncertainty as to possible pharmacokinetic/pharmacodynamic interactions and the concern about cardiotoxicity, the high activity of anthracyclinepaclitaxel regimens has prompted the investigators to explore their role in the adjuvant setting. Two pilot studies have demonstrated the feasibility of sequential high-dose therapy with cyclophosphamide, doxorubicin and paclitaxel [51, 52]; however, only randomized trials will ultimately clarify the potential efficacy of anthracycline-paclitaxel regimens as adjuvant therapy (Table 2). Conclusions Available data clearly indicate that: 1) anthracycline-paclitaxel regimens are extremely active; the preliminary results of anthracycline-
1. A'Hern RP, Smith IE, Ebbs SR. Chemotherapy and survival in advanced breast cancer: the inclusion of doxorubicin in coopertype regimens. Br J Cancer 1993; 67: 801-5. 2. Greenberg PAC, Hortobagyi G, Smith TL et al. Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 1996; 14: 2197-205. 3. Levine M, Branwell V, Bowman D et al. A clinical trial of intensive CEF versus CMF in premenopausal women with nodepositive breast cancer. Proc Am Soc Clin Oncol 1995; 14: 103. 4. Coombs RC, Bliss JM, Wils J et al. Adjuvant cyclophosphamide, methotrexate and fluorouracil versus fluorouracil, epirubicin and cyclophosphamide chemotherapy in premenopausal women with axillary node positive operable breast cancer: Results of a randomized trial. J Clin Oncol 1996; 14: 35-45. 5. Misset JL, di Palma M, Delgado M et al. Adjuvant treatment of node positive breast cancer with cycloposphamide, doxorubicin, fluorouracil and vincristine versus cyclophosphamide, methotrexate and fluorouracil: Final report after 16 year median follow-up duration. J Clin Oncol 1996; 14: 1136-45. 6. Perloff M, Norton L, Korzun AH et al. Post-surgical adjuvant chemotherapy of stage II breast carcinoma with or without crossover to a non-cross-resistant regimen; a Cancer and Leukemia Group B study. J Clin Oncol 1996; 14: 1589-98.
942 7. Wils J, Bliss JM, Coombs RC et al A multicentre randomized trial of tamoxifen versus tamoxifen plus epirubicin in postmenopausal women with node positive breast cancer. Proc Am Soc Clin Oncol 1996; 15: 101. 8. Seidman AD. The emerging role of paclitaxel in breast cancer therapy. Clin Cancer Res 1996; 1: 247-56. 9. Seidman AD, Reichman BS, Crown JPA et al. Paclitaxel as second and subsequent therapy for metastatic breast cancer: Activity independent of prior anthracycline response. J Clin Oncol 1995; 13:1152-9. 10. Nabholtz JM, Gelman K, Bontenbal et al. Multicenter randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 1996; 14: 1858-67. 11. Fisherman JS, Cowan KH, Noone K et al. Phase I—II study of 72 hour infusional paclitaxel and doxorubicin with granulocytestimulating-factor in patients with metastatic breast cancer. J Clin Oncol 1996; 14: 774-82. 12. Holmes FA, Madden T, Newman RA et al. Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1996; 14: 2713-21. 13. Sledge GW Jr, Robert M, Sparano JA et al. Paclitaxel (taxol)doxorubicin combinations in advanced breast cancer: The Eastern Cooperative Oncology Group experience. Semin Oncol 1994; 21 (Suppl 8): 15-8. 14. Hann SM, Liebmann JE, Cook J et al Taxol in combination with doxorubicin and etoposide: Possible antagonism in vitro. Cancer 1993; 72: 2705-11. 15. Akutsu M, Kano Y, Tsunoda S et al. Schedule dependent interaction between paclitaxel and doxorubicin in human cancer cell lines in vitro. Eur J Cancer 1995; 31A: 2341-6. 16. Madden T, Newman RA, Van NT. Sequence-dependent synergy of paclitaxel and doxorubicin in human breast carcinoma cells. Proc Am Ass Cancer Res 1995; 36: 2139. 17. Koechli OR, Sevin BU, Perras JP et al. Characteristics of the combination paclitaxel plus doxorubicin in breast cancer cell lines analyzed with the ATP-cell viability assay. Breast Cancer Res Treat 1993; 28: 21-7. 18. Gianni L, Kearns CM, Giani A et al. Non-linear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/ pharmacodynamic relationships in humans. J Clin Oncol 1995; 13: 180-90. 19. Liebmann E, Cook JH, Lipschultz C et al. Cytotoxic studies of paclitaxel (taxol) in human tumor cell lines. Br J Cancer 1993; 68. 1104-9. 20. Millward LK, Cosson EJ, Stokes KH, Mac Callum P. Cremophor EL changes the pharmacokinetics of doxorubicin. Proc Am Ass Cancer Res 1995; 36: 373. 21. Berg SL, Cowan KH, Bolis FM et al. Pharmacokinetics of taxol and doxorubicin administered alone and in combination by continuous 72 hour infusion. J Natl Cancer Inst 1994; 86: 143-5. 22. Gianni L. Theoretical and practical aspects of paclitaxel scheduling. Ann Oncol 1995; 6: 861-3. 23. Eisenhauer EH, ten Bokkel Huinink W, Swenerton KD et al. European-Canadian randomized trial of taxol in relapsed ovarian cancer: High vs. low dose and long vs. short infusion. J Clin Oncol 1994; 12: 2654-66. 24. Hainsworth JD, Greco FA. Paclitaxel administered by 1 hour infusion: preliminary results of a phase I—II trial comparing two schedules. Cancer 1994; 74: 1377-82. 25. Gianni L, Munzone E, Capri G et al. Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 1995; 13: 2688-99. 26. Gehl J, Boesgard M, PaaskeTet al. Combined doxorubicin and paclitaxel in advanced breast cancer: Effective and cardiotoxic. Ann Oncol 1996; 7: 687-93. 27. Amadori D, Frassineti GL, Zoli W et al. A phase 1/II study of
28.
29. 30.
31.
32.
33. 34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
sequential doxorubicin and paclitaxel in the treatment of advanced breast cancer. Ann Oncol 1996; 23 (Suppl 11): 16-22 Von Hoff DD, Layard MW, Basa P et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979, 91: 710-7. Praga C, Beretta G, Vigo P et al. Adriamycin cardiotoxicity: A survey of 1273 patients. Cancer Treat Rep 1979; 63: 827-34. Gianni L, Vigano L, Locatelli A et al. Different interference of paclitaxel (PTX) on human pharmacokinetics of doxorubicin and epirubicin (Epi). Proc Am Soc Clin Oncol 1997; 16: 786. Camaggi LM, Comparsi R, Strocchi E et al. Epirubicin and doxorubicin comparative metabolism and pharmacokinetics. A cross over study. Cancer Chemother Pharmacol 1988; 21: 221-8. Mross K, Maessen P, Van der Vijgh WJF et al. Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans. J Clin Oncol 1988; 6: 517-26. Bonadonna G, Gianni L, Santoro A et al. Drugs ten years later: Epirubicin. Ann Oncol 1993; 4: 359-69. Conte PF, Michelotti A, Baldini E et al. A dose-finding study of epirubicin in combination with paclitaxel in the treatment of advanced breast cancer. Sem Oncol 1996; 5 (Suppl 11): 28-31 Catimel G, Spielmann M, Dieras V et al. Phase I study of paclitaxel and epirubicin in patients with metastatic breast cancer. A preliminary report on safety. Semin Oncol 1996; 23 (Suppl 1): 24-7. Luck HJ, Thomssenn C, duBois A et al. Interim analysis of a phase II study of epirubicin and paclitaxel as first-line therapy in patients with metastatic breast cancer. Semin Oncol 1996; 23 (Suppl 1): 33-6. Conte PF, Baldini E, Gennari A et al. Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over three hours. A regimen with high activity and low cardiotoxicity in advanced breast cancer. J Clin Oncol 1997; 15: 2510-7. Minotti G, Cavaliere AF, Mordente A et al. Secondary alcohol metabolites mediate iron delocalization in cytosolic fractions of myocardial biopsies exposed to anticancer anthracyclines. Novel linkage between anthracycline metabolism and iron-induced cardiotoxicity. J Clin Invest 1995; 95 (4): 1595-605. Venturini M, Bruzzi P, Del Mastro L et al. Effect of adjuvant chemotherapy with or without anthracyclines on the activity and efficacy of first-line CEF regimen in patients with metastatic breast cancer. J Clin Oncol 1996; 14: 764-73 Neri B, Pacini P, Algeri R et al. Conventional versus high-dose epidoxorubicin as single agent in advanced breast cancer. Cancer Invest 1993; 11: 106-12. Focan C, Andrien JM, Closon MTet al. Dose-response relationship of epirubicin-based first-line chemotherapy for advanced breast cancer: A prospective randomized trial. J Clin Oncol 1993; 11: 1253-63. Bastholt L, Dalmar KM, Gjedde S et al. Epirubicin at four different dose levels in metastatic breast cancer. A randomized trial. J Clin Oncol 1996, 14: 1146-55. Brufman G, Colanjori E, Ghilezan M et al. Doubling epirubicin dose intensity (100 mg/sqm versus 50 mg/sqm) in the FEC regimen significantly increases response rates. An international randomized phase III study in metastatic breast cancer. Ann Oncol 1997; 8: 155-62. Bonncterre J, Roche H, Bremond A et al. A randomized trial of adjuvant chemotherapy with FEC 50 vs. FEC 100 for nodepositive operable breast cancer. Early report. Proc Am Soc Clin Oncol 1996; 15: 82. Gianni L, Kearns CM, Giani A et al. Non-linear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/ pharmacodynamic relationship in humans. J Clin Oncol 1995; 6: 180-90. Tomiak E, Piccart M, Mignolet F et al. Characterization of complete responders to combination chemotherapy for advanced breast cancer: A retrospective EORTC Breast Group Study. Eur J Cancer 1996; 32A: 1876-87. Decker DA, Ahlmann DL, Bisel HE Complete responders to
943
48.
49.
-50.
51.
52.
chemotherapy in metastatic breast cancer. JAMA 1979; 242: 2075-9. Nemoto T. Metastatic breast cancer: prolonged complete remission or possible cure with chemotherapy. Proc Am Soc Clin Oncol 1983; 2: 110. Sledge GW. Should we dream the impossible dream? The meaning of long-term survival in metastatic breast cancer. J Clin Oncol 1996; 14: 2191-3. -Bengaia C,- PazzagH VTibaldi C -et—al. Mobilization, collection and characterization of PBSC after epirubicin + paclitaxel plus G-CSF, in metastatic breast cancer. Cancer (in press). Demetri GB, Berry D, Younger J et al. Dose intensified cyclophosphamide-doxorubicin followed by taxol as adjuvant systemic chemotherapy for node-positive breast cancer (CALGB 9141): randomized comparison of two dose levels of G-CSF. Proc Am Soc Clin Oncol 1997; 16: 503. Hudis C, Seidman A, Baselga J et al. Sequence high-dose adjuvant doxorubicin, paclitaxel and cyclophosphamide with G-CSF
is feasible for women with resected breast cancer and > 4 lymphnodes. Proc Am Soc Clin Oncol 1994; 13: 62. 53. Burgeois H, Gruia G, Dieras V et al. Docetaxel in combination with doxorubicin as 1st line chemotherapy of metastatic breast cancer: A phase I dose finding study. Proc Am Soc Clin Oncol 1996; 15: 258. Received 9 April 1997; accented 12 August 1997..
Correspondence to: P. F. Conte, MD U.O. Oncologia Medica Ospedale Santa Chiara Via Roma 67 56100 Pisa Italy
Review Anthracyclines-paclitaxel combinations in the treatment of breast cancer P. F. Conte & A. Gennari Department of Oncology, Division of Medical Oncology, St. Chiara Hospital, Pisa, Italy
Key words: breast cancer, Taxol-anthracycline combination
Introduction
The incorporation of anthracyclines in combination regimens has increased the response rates, remission duration and survival of patients with advanced breast cancer [1], with approximately 20% of the patients still disease-free 10 years after achievement of complete response [2]. Moreover, at least in some trials, in patients with early breast cancer anthracycline-based adjuvant chemotherapy has produced better relapse-free survival and survival than CMF or tamoxifen [3-7]. These data indicate that the prognosis of early and advanced breast cancer can be improved by incorporating the more active drugs in combination regimens. On these premises the activity of paclitaxel has evoked considerable interest: as a single agent it has produced a response rate higher than 50% in chemonaive patients [8] and as high as 20%-30% in patients previously treated with anthracyclines [9, 10]. Doxorubicin-paclitaxel combinations Because of its high level of activity and non-complete cross-resistance, several trials have been performed to evaluate the feasibility and toxic effects of doxorubicin combined with paclitaxel. The early phase I—II studies used paclitaxel by prolonged infusion (24 or 72 hours) with doxorubicin given concomitantly for 72 hours [11], by 48-hour infusion immediately before or after paclitaxel [12] or as an i.v. bolus four hours before or after paclitaxel [13]. With these regimens the dose-limiting toxicities (mucositis, febrile neutropenia, typhlitis) appear at relatively low doses and are schedule-dependent, with doxorubicin followed by paclitaxel being less toxic. Moreover, the overall and complete response rates were lower than expected, suggesting that the cytotoxicity of this combination is subcumulative. Subsequent to these trials, preclinical studies have shown conflicting data on the interactions between doxorubicin and paclitaxel in vitro, with some studies demonstrating sub-cumulative cytotoxicity and
others sequence-dependent synergy [14-17]. Apart from possible cytotoxic interactions, other factors may contribute to the suboptimal activity of this regimen: the non-linear pharmacokinetics of paclitaxel [18], the presence of Cremophor EL which might alter the cytotoxicity of the taxane and the intracellular concentration of anthracycline [19, 20] and the alteration of doxorubicin pharmacokinetics induced by prior or concomitant paclitaxel [12, 21, 22]. Following the demonstration of the safety and activity of paclitaxel given as short infusions [23, 24], European investigators have performed trials using bolus doxorubicin and paclitaxel over three hours. The most relevant findings of these studies were: the lack of sequence-dependent toxicity [25], the high incidence of symptomatic CHF [25, 26] and the striking antitumor activity, with a response rate in the range of 90% and a complete remission rate as high as 24%—41% [25—27]. The antitumor activity and the cardiac effects of this combination suggested the possibility of a therapeutic and toxic enhancement between the two drugs. As for cardiotoxicity, in two studies [25, 26] 13 of 64 patients (20%) developed a CHF; seven of these patients had personal risk factors for cardiopathic disease but only one died because of cardiomyopathy. The cardiotoxic events occurred at median cumulative doxorubicin doses of 392-480 mg/sqm, well below the maximum recommended cumulative doses of 550 mg/sqm [28, 29]. On the basis of these results the maximum cumulative dose of bolus doxorubicin in combination with paclitaxel over three hours should not exceed 360 mg/sqm. The enhanced cardiotoxicity of this combination can be explained by the reduced elimination of doxorubicinol induced by paclitaxel at the hepatic level [30]. It is of interest that when doxorubicin was given 16 hours before paclitaxel no cardiotoxic events occurred [27]; this interval of administration corresponds to the initial and intermediate half-lives of doxorubicin and doxorubicinol [31, 32] Ongoing trials will clarify whether a time interval between administrations of doxorubicin and paclitaxel is necessary and if so, how long it should be, for main-
940 tenance of cytotoxicity and restriction of cardiotoxicity (Table 1). Epirubicin-paclitaxel combinations Apart from schedule-optimization and lower cumulative doses of doxorubicin, the cardiotoxicity of the anthracycline-taxane combination might be reduced by employing a less cardiotoxic analog. Epirubicin seems particularly attractive because of its antitumor activity, which is similar to that of the parent compound, with reduced cardiotoxicity and mucositis [33]. The dose-finding studies of the epirubicin-paclitaxel combination were started when the preliminary data of doxorubicin-paclitaxel were already available, so the investigators administered the taxane as a short infusion and the patients were carefully monitored for potential cardiotoxicity. Some of these studies have been completed and the most striking feature is the lack of cardiac toxicity: only 6% of the patients showed a decline of the left ventricular ejection fraction below 50% and developed a mild congestive heart failure; in particular, only three of our patients experienced a grade 3 cardiotoxicity, the first two at cumulative epirubicin doses of 720 and 1080 mg/sqm, and the third after 540 mg/sqm cumulative epirubicin followed by high-dose chemotherapy [34-37]. The excellent cardiac tolerability of this combination cannot be explained solely on the basis of the lower cardiotoxic effects of epirubicin. Additional explanations could be a better selection of the patients and, at least in two trials [35, 36], the use of low epirubicin doses. However, very recent studies from Gianni et al. [30] and our group [37] have shown that the co-administration of epirubicin and paclitaxel induces an increased glucurunidation of epirubicin, leading to increased urinary elimination and decreased plasma levels of epirubicinol; these secondary alcohol metabolites (doxorubicinol and epirubicinol) have been shown to play an important role in the pathogenesis of cardiac damage [38]. Therefore, the pharmacokinetic interferences of anthracycline-paclitaxel are completely different according to the anthracycline employed, with the doxorubicin-paclitaxel combination showing a potentiation of cardiotoxicity that is not observed with the epirubicin-paclitaxel combinations. The logical question then is: do these pharmacokinetic interferences alter the antitumor activity of the combination? In two trials the overall and the complete response rates were 44%-50% and less than 10%, respectively [35, 36]; in our trial the overall response rate was 84% but the rate of complete remissions was 19% only [37]. These response rates and particularly that of the complete responses are lower than those reported with the doxorubicin-paclitaxel regimens; however, there are profound differences in the characteristics of the patients and in the anthracycline dosages across these studies.
Table 1. Anthracyclines-paclitaxel as first-line therapy in advanced breast cancer: ongoing randomized trials. Study group
Study design
EORTC SWOG Eastern Europe NL, Germany GONO ECOG
A 60 + P 175 vs. A 60 + C 600 A 60 + P 200 vs. A 60 + C 750 A 50 -> 24 hrs - P 220 vs. FAC (500/50/500) A 60 + P 200 vs. E 90 + P 200 E 90 + P 200 vs. E 120 x 4 - . P 250 x 4 P -• A vs. A -• Pvs. A + P
Abbreviations: A - doxorubicin; P - paclitaxel (over 3 hrs); F - 5-FU; C - cyclophosphamide; E - epirubicin. All doses are mg/sqm.
In the doxorubicin-paclitaxel trials 72% of the patients were chemo-naive and most of them had never received any kind of endocrine therapy; by contrast, in the epirubicin-paclitaxel studies 60% of the patients had failed adjuvant chemotherapy which in some cases included anthracyclines, and a significant number of them were pretreated with hormonal therapy for advanced disease. A multivariate analysis has recently demonstrated that these pretreatments have a significant impact on the probability of response [39]. Moreover, in two studies the majority of the patients were treated with epirubicin doses of 50 to 60 mg/sqm [35, 36]. Several randomized trials in early and advanced breast cancer have demonstrated for epirubicin a significant dose-effect relationship up to doses of 90-100 mg/sqm [40-44]. In contrast, in the doxorubicin trials the dose of anthracycline was 60 mg/sqm, which corresponds to the 90 mg/sqm of epirubicin we used in our study. Apart from the patients' characteristics and the dose issue, other data must be analysed to determine whether the co-administration of epirubicin and paclitaxel modifies the cytotoxicity of the two drugs. The pharmacokinetic of paclitaxel when given as a single agent is nonlinear and its pharmacodynamic effects, particularly neutropenia, are non-linearly related to the time that paclitaxel spends above the threshold plasma concentration of 0.05 urn [45]. On the other hand, in our study the severity and duration of neutropenia were not significantly related to the administered dose of paclitaxel or to the time spent above the threshold plasma concentration [37]. Together the pharmacokinetic data and the pharmacodynamic effects indicate that the co-administration of epirubicin with paclitaxel does not compromise the cardiac tolerability of the anthracycline and modifies the relationship between paclitaxel plasma concentration and neutropenia. Therefore, we cannot exclude the possibility that the combination of the two drugs results in sub-additive antitumor activity. To clarify this point, we are presently conducting a randomized trial comparing eight courses of epirubicinpaclitaxel given in combination to four courses of fulldose epirubicin (120 mg/sqm) followed by four courses of paclitaxel (250 mg/sqm over three hours) (Table 1).
941 Even if the question of the 'best schedule' is still open, these studies demonstrate that an anthracycline plus paclitaxel is probabily the most active regimen available in the treatment of advanced breast cancer. Role of anthracycline-paclitaxel in the management of advanced breast cancer ~~ ~ ~~ Outside clinical trials, the biological and economic costs of these regimens must be taken into account when defining their role in the management of breast cancer. Up to now in advanced breast cancer chemotherapy has been mainly given for palliation in patients with hormone-resistant and rapidly progressive visceral disease. However, two recently published papers have reported that approximatively 20% of women with metastatic breast cancer who have achieved a clinical complete remission with standard-dose chemotherapy have survived free of disease for more than five years [2, 46]. Worthy of note is the fact that such prolonged disease-free survivals have never been observed with non-anthracycline-based regimens [47, 48]. Will the complete remissions obtained with anthracycline-paclitaxel be as durable as those achieved with other anthracyclin-based regimens? If so, we should really 'dream the impossible dream' of treating some patients with curative intent [49]. Such a dream could transmute into reality if the role of high-dose chemotherapy with hemopoietic stem cell support is confirmed by ongoing randomized trials. In this setting the epirubicin-paclitaxel combination is of particular interest; in fact this regimen is very effective in mobilizing peripheral blood progenitors [50], and patients can be treated with 6 courses of induction epirubicin-paclitaxel followed by a myeloablative course of thiotepa-melphalan with good cardiac tolerance.
Table 2 Anthracyclines-taxanes as adjuvant chemotherapy: ongoing randomized trials. Study group
Study design
CALGB ECTO (INT Milan)
A (60 vs. 75 vs. 90) C x 4 ± P x 4 Surgery + A x 4 + CMF x 4 vs. Surgery + AP * 4T- C M F M vs. AP x 4 + CMF x 4 + surgery AC x 4 ± P x 4 EP x 4 vs. CEF x 6 E x 6 vs. E x 3 + D x 3
--
—
-
-
-
NSABP GONO ICCG
Abbreviations. A - doxorubicin; P - paclitaxel (over 3 hrs); F - 5-FU; C - cyclophosphamide; E - epirubicin; D - docetaxel; M - methotrexate.
docetaxel combination also appear very promising [53]. 2) the short infusion of paclitaxel is the preferred one in combination; 3) the short infusion of paclitaxel is still associated with altered pharmacokinetics of doxorubicin and epirubicin that is different for the two drugs. These pharmacokinetic differences may be relevant both in terms of cardiotoxicity and activity; 4) the pharmacokinetic interactions between paclitaxel and other drugs should be considered before planning clinical trials. Acknowledgement Supported in part by a grant from AIRC (Associazione Italiana Ricerca Cancro). References
Future developments In spite of the uncertainty as to possible pharmacokinetic/pharmacodynamic interactions and the concern about cardiotoxicity, the high activity of anthracyclinepaclitaxel regimens has prompted the investigators to explore their role in the adjuvant setting. Two pilot studies have demonstrated the feasibility of sequential high-dose therapy with cyclophosphamide, doxorubicin and paclitaxel [51, 52]; however, only randomized trials will ultimately clarify the potential efficacy of anthracycline-paclitaxel regimens as adjuvant therapy (Table 2). Conclusions Available data clearly indicate that: 1) anthracycline-paclitaxel regimens are extremely active; the preliminary results of anthracycline-
1. A'Hern RP, Smith IE, Ebbs SR. Chemotherapy and survival in advanced breast cancer: the inclusion of doxorubicin in coopertype regimens. Br J Cancer 1993; 67: 801-5. 2. Greenberg PAC, Hortobagyi G, Smith TL et al. Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 1996; 14: 2197-205. 3. Levine M, Branwell V, Bowman D et al. A clinical trial of intensive CEF versus CMF in premenopausal women with nodepositive breast cancer. Proc Am Soc Clin Oncol 1995; 14: 103. 4. Coombs RC, Bliss JM, Wils J et al. Adjuvant cyclophosphamide, methotrexate and fluorouracil versus fluorouracil, epirubicin and cyclophosphamide chemotherapy in premenopausal women with axillary node positive operable breast cancer: Results of a randomized trial. J Clin Oncol 1996; 14: 35-45. 5. Misset JL, di Palma M, Delgado M et al. Adjuvant treatment of node positive breast cancer with cycloposphamide, doxorubicin, fluorouracil and vincristine versus cyclophosphamide, methotrexate and fluorouracil: Final report after 16 year median follow-up duration. J Clin Oncol 1996; 14: 1136-45. 6. Perloff M, Norton L, Korzun AH et al. Post-surgical adjuvant chemotherapy of stage II breast carcinoma with or without crossover to a non-cross-resistant regimen; a Cancer and Leukemia Group B study. J Clin Oncol 1996; 14: 1589-98.
942 7. Wils J, Bliss JM, Coombs RC et al A multicentre randomized trial of tamoxifen versus tamoxifen plus epirubicin in postmenopausal women with node positive breast cancer. Proc Am Soc Clin Oncol 1996; 15: 101. 8. Seidman AD. The emerging role of paclitaxel in breast cancer therapy. Clin Cancer Res 1996; 1: 247-56. 9. Seidman AD, Reichman BS, Crown JPA et al. Paclitaxel as second and subsequent therapy for metastatic breast cancer: Activity independent of prior anthracycline response. J Clin Oncol 1995; 13:1152-9. 10. Nabholtz JM, Gelman K, Bontenbal et al. Multicenter randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 1996; 14: 1858-67. 11. Fisherman JS, Cowan KH, Noone K et al. Phase I—II study of 72 hour infusional paclitaxel and doxorubicin with granulocytestimulating-factor in patients with metastatic breast cancer. J Clin Oncol 1996; 14: 774-82. 12. Holmes FA, Madden T, Newman RA et al. Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1996; 14: 2713-21. 13. Sledge GW Jr, Robert M, Sparano JA et al. Paclitaxel (taxol)doxorubicin combinations in advanced breast cancer: The Eastern Cooperative Oncology Group experience. Semin Oncol 1994; 21 (Suppl 8): 15-8. 14. Hann SM, Liebmann JE, Cook J et al Taxol in combination with doxorubicin and etoposide: Possible antagonism in vitro. Cancer 1993; 72: 2705-11. 15. Akutsu M, Kano Y, Tsunoda S et al. Schedule dependent interaction between paclitaxel and doxorubicin in human cancer cell lines in vitro. Eur J Cancer 1995; 31A: 2341-6. 16. Madden T, Newman RA, Van NT. Sequence-dependent synergy of paclitaxel and doxorubicin in human breast carcinoma cells. Proc Am Ass Cancer Res 1995; 36: 2139. 17. Koechli OR, Sevin BU, Perras JP et al. Characteristics of the combination paclitaxel plus doxorubicin in breast cancer cell lines analyzed with the ATP-cell viability assay. Breast Cancer Res Treat 1993; 28: 21-7. 18. Gianni L, Kearns CM, Giani A et al. Non-linear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/ pharmacodynamic relationships in humans. J Clin Oncol 1995; 13: 180-90. 19. Liebmann E, Cook JH, Lipschultz C et al. Cytotoxic studies of paclitaxel (taxol) in human tumor cell lines. Br J Cancer 1993; 68. 1104-9. 20. Millward LK, Cosson EJ, Stokes KH, Mac Callum P. Cremophor EL changes the pharmacokinetics of doxorubicin. Proc Am Ass Cancer Res 1995; 36: 373. 21. Berg SL, Cowan KH, Bolis FM et al. Pharmacokinetics of taxol and doxorubicin administered alone and in combination by continuous 72 hour infusion. J Natl Cancer Inst 1994; 86: 143-5. 22. Gianni L. Theoretical and practical aspects of paclitaxel scheduling. Ann Oncol 1995; 6: 861-3. 23. Eisenhauer EH, ten Bokkel Huinink W, Swenerton KD et al. European-Canadian randomized trial of taxol in relapsed ovarian cancer: High vs. low dose and long vs. short infusion. J Clin Oncol 1994; 12: 2654-66. 24. Hainsworth JD, Greco FA. Paclitaxel administered by 1 hour infusion: preliminary results of a phase I—II trial comparing two schedules. Cancer 1994; 74: 1377-82. 25. Gianni L, Munzone E, Capri G et al. Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 1995; 13: 2688-99. 26. Gehl J, Boesgard M, PaaskeTet al. Combined doxorubicin and paclitaxel in advanced breast cancer: Effective and cardiotoxic. Ann Oncol 1996; 7: 687-93. 27. Amadori D, Frassineti GL, Zoli W et al. A phase 1/II study of
28.
29. 30.
31.
32.
33. 34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
sequential doxorubicin and paclitaxel in the treatment of advanced breast cancer. Ann Oncol 1996; 23 (Suppl 11): 16-22 Von Hoff DD, Layard MW, Basa P et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979, 91: 710-7. Praga C, Beretta G, Vigo P et al. Adriamycin cardiotoxicity: A survey of 1273 patients. Cancer Treat Rep 1979; 63: 827-34. Gianni L, Vigano L, Locatelli A et al. Different interference of paclitaxel (PTX) on human pharmacokinetics of doxorubicin and epirubicin (Epi). Proc Am Soc Clin Oncol 1997; 16: 786. Camaggi LM, Comparsi R, Strocchi E et al. Epirubicin and doxorubicin comparative metabolism and pharmacokinetics. A cross over study. Cancer Chemother Pharmacol 1988; 21: 221-8. Mross K, Maessen P, Van der Vijgh WJF et al. Pharmacokinetics and metabolism of epidoxorubicin and doxorubicin in humans. J Clin Oncol 1988; 6: 517-26. Bonadonna G, Gianni L, Santoro A et al. Drugs ten years later: Epirubicin. Ann Oncol 1993; 4: 359-69. Conte PF, Michelotti A, Baldini E et al. A dose-finding study of epirubicin in combination with paclitaxel in the treatment of advanced breast cancer. Sem Oncol 1996; 5 (Suppl 11): 28-31 Catimel G, Spielmann M, Dieras V et al. Phase I study of paclitaxel and epirubicin in patients with metastatic breast cancer. A preliminary report on safety. Semin Oncol 1996; 23 (Suppl 1): 24-7. Luck HJ, Thomssenn C, duBois A et al. Interim analysis of a phase II study of epirubicin and paclitaxel as first-line therapy in patients with metastatic breast cancer. Semin Oncol 1996; 23 (Suppl 1): 33-6. Conte PF, Baldini E, Gennari A et al. Dose-finding study and pharmacokinetics of epirubicin and paclitaxel over three hours. A regimen with high activity and low cardiotoxicity in advanced breast cancer. J Clin Oncol 1997; 15: 2510-7. Minotti G, Cavaliere AF, Mordente A et al. Secondary alcohol metabolites mediate iron delocalization in cytosolic fractions of myocardial biopsies exposed to anticancer anthracyclines. Novel linkage between anthracycline metabolism and iron-induced cardiotoxicity. J Clin Invest 1995; 95 (4): 1595-605. Venturini M, Bruzzi P, Del Mastro L et al. Effect of adjuvant chemotherapy with or without anthracyclines on the activity and efficacy of first-line CEF regimen in patients with metastatic breast cancer. J Clin Oncol 1996; 14: 764-73 Neri B, Pacini P, Algeri R et al. Conventional versus high-dose epidoxorubicin as single agent in advanced breast cancer. Cancer Invest 1993; 11: 106-12. Focan C, Andrien JM, Closon MTet al. Dose-response relationship of epirubicin-based first-line chemotherapy for advanced breast cancer: A prospective randomized trial. J Clin Oncol 1993; 11: 1253-63. Bastholt L, Dalmar KM, Gjedde S et al. Epirubicin at four different dose levels in metastatic breast cancer. A randomized trial. J Clin Oncol 1996, 14: 1146-55. Brufman G, Colanjori E, Ghilezan M et al. Doubling epirubicin dose intensity (100 mg/sqm versus 50 mg/sqm) in the FEC regimen significantly increases response rates. An international randomized phase III study in metastatic breast cancer. Ann Oncol 1997; 8: 155-62. Bonncterre J, Roche H, Bremond A et al. A randomized trial of adjuvant chemotherapy with FEC 50 vs. FEC 100 for nodepositive operable breast cancer. Early report. Proc Am Soc Clin Oncol 1996; 15: 82. Gianni L, Kearns CM, Giani A et al. Non-linear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/ pharmacodynamic relationship in humans. J Clin Oncol 1995; 6: 180-90. Tomiak E, Piccart M, Mignolet F et al. Characterization of complete responders to combination chemotherapy for advanced breast cancer: A retrospective EORTC Breast Group Study. Eur J Cancer 1996; 32A: 1876-87. Decker DA, Ahlmann DL, Bisel HE Complete responders to
943
48.
49.
-50.
51.
52.
chemotherapy in metastatic breast cancer. JAMA 1979; 242: 2075-9. Nemoto T. Metastatic breast cancer: prolonged complete remission or possible cure with chemotherapy. Proc Am Soc Clin Oncol 1983; 2: 110. Sledge GW. Should we dream the impossible dream? The meaning of long-term survival in metastatic breast cancer. J Clin Oncol 1996; 14: 2191-3. -Bengaia C,- PazzagH VTibaldi C -et—al. Mobilization, collection and characterization of PBSC after epirubicin + paclitaxel plus G-CSF, in metastatic breast cancer. Cancer (in press). Demetri GB, Berry D, Younger J et al. Dose intensified cyclophosphamide-doxorubicin followed by taxol as adjuvant systemic chemotherapy for node-positive breast cancer (CALGB 9141): randomized comparison of two dose levels of G-CSF. Proc Am Soc Clin Oncol 1997; 16: 503. Hudis C, Seidman A, Baselga J et al. Sequence high-dose adjuvant doxorubicin, paclitaxel and cyclophosphamide with G-CSF
is feasible for women with resected breast cancer and > 4 lymphnodes. Proc Am Soc Clin Oncol 1994; 13: 62. 53. Burgeois H, Gruia G, Dieras V et al. Docetaxel in combination with doxorubicin as 1st line chemotherapy of metastatic breast cancer: A phase I dose finding study. Proc Am Soc Clin Oncol 1996; 15: 258. Received 9 April 1997; accented 12 August 1997..
Correspondence to: P. F. Conte, MD U.O. Oncologia Medica Ospedale Santa Chiara Via Roma 67 56100 Pisa Italy