Anthracyclines are among the most active agents in the treatment of metastatic breast cancer (MBC), and are components of many regimens that have been shown to be more effective than regimens based on CMF (cyclophosphamide, methotrexate, fluorouracil). In addition, the metanalysis of Early Breast Cancer Trialists Collaborative Group demonstrated that anthracycline-based adjuvant polychemotherapy (e.g., with FAC [fluorouracil, doxorubicin, cyclophosphamide] or FEC [fluorouracil, epirubicin, cyclophosphamide]) reduces the annual breast cancer death rate by ∼ 38% for women younger than 50 years and by ∼ 20% for those of age 50–69 years. Despite this success, relapse after adjuvant chemotherapy remains a critical problem, and the rate of MBC cancer patients who have already received anthracyclines as adjuvant or neoadjuvant will increase. The extensive use of anthracyclines in the adjuvant setting increases the possibility of selecting cellular clones with intrinsic resistance to anthracyclines or of inducing development of acquired multidrug resistance. Moreover, the cumulative dose-related risk of cardiotoxicity could be a major limitation to the use of conventional anthracyclines in patients with MBC who received an adjuvant treatment with anthracyclines. Both phenomena could act against the opportunity of retreatment with antracyclines when metastatic disease is diagnosed. Published reports show conflicting results and leave open the question of whether an anthracycline-containing regimen is worthy as first-line treatment for MBC patients pretreated with adjuvant or neoadjuvant anthracyclines. This issue is particularly relevant for HER-2-negative MBC patients, because for women with MBC whose tumors are HER-2-positive the concurrent administration of anthracycline with trastuzumab is limited by a high rate of cardiotoxicity. In this overview, we summarize the results observed with first-line anthracycline-containing regimens in patients with MBC treated with adjuvant anthracyclines and discuss the current options of first-line therapy for these patients.
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References
Albain, K.S., Nag, S., Calderillo-Ruiz, G., Jordaan, J.P, Llombart, A., Pluzanska, A., Pawlicki, M., Melemed, A.S., O'Shaughnessy, J., and Reyes J.M. 2004. Global phase III study of gemcit-abine plus paclitaxel (GT) vs. paclitaxel (T) as frontline therapy for metastatic breast cancer (MBC): first report of overall survival. J. Clin. Oncol. 22: 14 S (Abstr.510)
Al-Batran, S.E., Bischoff, J., von Minckwitz, G., Atmaca, A., Kleeberg, U., Meuthen, I., Morack, G., Lerbs, W., Hecker, D., Sehouli, J., Knuth, A., and Jager, E. 2006. The clinical benefit of pegylated liposomal doxorubicin in patients with metastatic breast cancer previously treated with conventional anthracyclines: a multicentre phase II trial. Br. J. Cancer 94: 1615–1620
Bartsch, R., Wenzel, C., Pluschnig, U., Hussian, D., Sevelda, U., Locker, G.J., Mader, R., Zielinski, C.C., and Steger, G.G. 2006. Oral vinorelbine alone or in combination with trastuzumab in advanced breast cancer: results from a pilot trial. Cancer Chemother. Pharmacol. 57: 554–558
Baselga, J., Carbonell, X., Castañeda-Soto, N.J., Clemens, M., Green, M., Harvey, V., Morales, S., Barton, C., and Ghahramaniet, P. 2005. Phase II study of efficacy, safety, and pharma-cokinetics of trastuzumab monotherapy administered on a 3-weekly schedule. J. Clin. Oncol. 23: 2162–2171
Batist, G., Harris, L., Azarnia, N., Lee, L.W., and Daza-Ramirez, P. 2006. Improved anti-tumor response rate with decreased cardiotoxicity of non-pegylated liposomal doxorubicin compared with conventional doxorubicin in first-line treatment of metastatic breast cancer in patients who had received prior adjuvant doxorubicin: results of a retrospective analysis. Anticancer Drugs 17: 587–595
Beslija, S., Obralic, N., Basic, H., Tatarevic, A., Naila, M., Banjin, M., Cardzic, A., Sosevic, A., Pasic, A., Ceric, T., and Salkic, B. 2006. Randomized trial of sequence vs. combination of capecitabine (X) and docetaxel (T): XT vs T followed by X after progression as first-line therapy for patients (pts) with metastatic breast cancer (MBC). J. Clin. Oncol. 24: 18 S (Abstr.571)
Bianchi, G., Albanell, J., Eiermann, W., Vitali, G., Borquez, D., Vigano', L., Molina, R., Raab, G., Locatelli, A., Vanhauwere, B., Gianni, L., and Baselga, J. 2003. Pilot trial of trastuzumab starting with or after the doxorubicin component of a doxorubicin plus paclitaxel regimen for women with HER2-positive advanced breast cancer. Clin. Cancer Res. 9: 5944–5951
Burstein, H.J., Harris, L.N., Marcom, P.K., Lambert-Falls, R., Havlin, K., Overmoyer, B., Friedlander, Jr., R.J., Gargiulo, J., Strenger, R., Vogel, C.L., Ryan, P.D., Ellis, M.J., Nunes, R.A., Bunnell, C.A., Campos, S.M., Hallor, M., Gelman, R., and Wineret, E.P. 2003. Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J. Clin. Oncol. 21: 2889–2895
Chan, S., Romieu, G., Huober, J., Delozier, T., Tubiana—Hulin, M., Lluch, A., Schneeweiss, A., Llombart, A., Carrasco, E., and Fumoleau, P. 2005. Gemcitabine plus docetaxel (GD) versus capecitabine plus docetaxel (CD) for anthracy-cline-pretreated metastatic breast cancer (MBC) patients (pts): results of a European phase III study. J. Clin. Oncol. 23: 16 S (Abstr. 581)
Chia, S., Clemons, M., Martin, L.A., Rodgers, A., Gelmon, K., Pond, G.R., and Panasciet, L. 2006. Pegylated liposomal doxorubicin and trastuzu-mab in HER-2 overexpressing metastatic breast cancer: a multicenter phase II trial. J. Clin. Oncol. 24: 2773–2778
Cortés, J., Climent, M.A., Lluch, A., Hornedo, J., Gascón, P., Mayordomo, J., Gil, M., Benavides, M., Regueiro, P. , Trigo, J., and Baselga, J. on behalf of the Solti Group. 2004. Updated results of a phase II study (M77035) of Myocet® combined with weekly Herceptin® and paclitaxel in patients with HER2-positive locally advanced or metastatic breast cancer (LABC/MBC). 27th Annual San Antonio Breast Cancer Symposium; (Abstr. 3041)
De Maio, E., Pacilio, C., Gravina, A., Morabito, A., Di Rella, F., Labonia, V. , Landi, G., Nuzzo, F., Rossi, E., Silvestro, P. , Botti, G., Di Bonito, M., Curcio, M.P., Formichelli, F., La Vecchia, F., Staiano, M., Maurea, N., D'Aiuto, G., D'Aiuto, M., Thomas, R., Signoriello, G., Perrone, F., and de Matteis, A. 2007. Vinorelbine plus 3-weekly trastuzumab in metastatic breast cancer. A single-centre phase 2 trial. BMC Cancer 7: 50
Di Leo A, Gomez H, Aziz Z, Zvirbule, Z., Arbushites, M., Oliva, C.R., Koehler, M., Williams, L.S., Dering, J., and Finn, R.S. 2007. Lapatinib (L) with paclitaxel compared to pacli-taxel as first-line treatment for patients with metastatic breast cancer: a phase III randomized double-blind study of 580 patients. J. Clin. Oncol. 25: 18 S (Abstr.1011)
Fountzilas, G., Kalofonos, H.P., Dafni, V. , Papadimitriou, C., Bafaloukos, D., Papakostas, P., Kalogera-Fountzila, A., Gogas, H., Aravantinos, G., Moulopoulos, L.A., Economopoulos, T., Pectasides, D., Maniadakis, N., Siafaka, V. , Briasoulis, E., Christodoulou, C., Tsavdaridis, D., Makrantonakis, P., Razis, E., Kosmidis, P., Skarlos, D., and Dimopoulos, M.A. 2004a. Paclitaxel and epirubicin versus paclitaxel and carboplatin as first line chemotherapy in patients with advanced breast cancer: a phase III study conducted by the Hellenic Cooperative Oncology Group. Ann. Oncol. 15: 1517–1526
Fountzilas, G., Christodoulou, C., Tsavdaridis, D., Kalogera-Fountzila, A., Aravantinos, G., Razis, E., Kalofonos, H.P., Papakostas, P., Karina, M., Gogas, H., and Skarlos, D. 2004b. Paclitaxel and gemcitabine, as first-line chemotherapy, combined with trastuzumab in patients with advanced breast cancer: a phase II study conducted by the Hellenic Cooperative Oncology Group (HeCOG). Cancer Invest. 22: 655–662
Gasparini, G., Gion, G., Mariani, L., Papaldo, P. , Crivellari, D., Filippelli, G., Morabito, A., Silingardi, V. , Torino, F., Spada, A., Cancan, M., De Sio, L., Caputo, A., Cognetti, F., Lambiase, A., and Amadori, D. 2007. Randomized Phase II Trial of weekly paclitaxel alone versus trastuzu-mab plus weekly paclitaxel as first-line therapy of patients with Her-2 positive advanced breast cancer. Breast Cancer Res. Treat. 101: 355–365
Gennari, A., Bruzzi, P., Orlandini, C., Salvatori, B., Donati, S., Landucci, E., Guarneri, V. , Rondini, M., Ricci, S., and Conte, P. 2004. Activity of first-line epirubicin and paclitaxel in metastatic breast cancer is independent of type of adjuvant therapy. Br. J. Cancer 90: 962–967
Geyer, C.E., Forster, J., Lindquist, D., Chan, S., Romieu, C.G., Pienkowski, T., Jagiello -Gruszfeld, A., Crown, J., Chan, A., Kaufman, B., Skarlos, D., Campone, M., Davidson, N., Berger, M., Oliva, C., Rubin, S.D., Stein, S., and Cameron, D. 2006. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N. Engl. J. Med. 355: 2733–2743
Jones, S.E., Erban, J., Overmoyer, B., Budd, G.T., Hutchins, L., Lower, E., Laufman, L., Sundaram, S., Urba, W.J., Pritchard, K.I., Mennel, R., Richards, D., Olsen, S., Meyers, M.L., and Ravdin, P.M. 2005. Randomized phase III trial of docetaxel compared with paclitaxel in metastatic breast cancer. J. Clin. Oncol. 23: 5542–5551
Kardinal, C.G., Perry, M.C., Korzun, A.H., Rice, M.A., Ginsberg, S., and Wood, W.C. 1988. Responses to chemotherapy or chemohormo-nal therapy in advanced breast cancer patients treated previously with adjuvant chemotherapy. Cancer 61: 415–419
Leonard, R., O'Shaughnessy, J., Vukelija, S., Gorbounova, V. , Chan-Navarro, C.A., Maraninchi, D., Barak-Wigler, N., McKendrick, J.J., Harker, W.G., Bexon, A.S., and Twelves, C. 2006. Detailed analysis of a randomized phase III trial: can the tolerability of capecitabine plus docetaxel be improved without compromising its survival advantage? Ann. Oncol. 17: 1379–1385
Martín, M., Ruiz, A., Muñoz, M., Balil, A., García-Mata, J., Calvo, L., Carrasco E., Mahillo, E., Casado, A., Ángel García-Saenz, J., Escudero, M.J., Guillem, V. , Jara, C., Ribelles, N., Salas, F., Soto, C., Morales-Vasquez, F., Rodríguez, C.A., Adrover, E., Mel, J.R. 2007. Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol. 8: 219–225
Marty, M., Cognetti, F., Maraninchi, D., Snyder, R., Mauriac, L., Tubiana-Hulin, M., Chan, S., Grimes, D., Anto'n, A., Lluch, A., Kennedy, J., O'Byrne, K., Conte, P.F., Green, M., Ward, C., Mayne, K., and Extra, J.M. 2005. Randomized phase II trial of the efficacy and safety of tras-tuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2—positive metastatic breast cancer administered as first-line treatment: the M77001 Study Group. J. Clin. Oncol. 23: 4265–4274
Mavroudis, D., Ardavanis, A., Boukovinas, I., Varthalitis, I., Syrigos, K., Potamianou, A., Kouroussis, C., and Georgoulias, V. 2006. A multicenter randomized study comparing vinore-lbine plus gemcitabine versus capecitabine mon-otherapy as salvage treatment in patients with advanced breast cancer pretreated with taxane and anthracycline chemotherapy: A preliminary report. J. Clin. Oncol. 24: 18 S (Abstr.658)
Miller, K.D., Wang, M., Gralow, J., Dickler, M., Cobleigh, M.A., Perez, E.A., Shenkier, T.N., and Davidson, N.E. 2005. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Breast Cancer Res. Treat. 94 (Suppl 1): S6 Abstr
Morabito, A., Filippelli, G., Palmeri, S., Cascinu, S., Ferraù, F., Zagonel, V., Gattuso, D., Catalano, V. , Capaccetti, B., Franciosi, V. , Accurso, V., Scinto, F., and Gasparini, G. 2003. The combination of gemcitabine and vinorelbine is an active regimen as second-line therapy in patients with metastatic breast cancer pretreated with taxanes and/or anthracyclines: a phase I-II study. Breast Cancer Res. Treat. 78: 29–36
Morabito, A., Longo, R., Gattuso, D., Carillio, G., Massaccesi, C., Mariani, L., Bonginelli, P. , Amici, S., De Sio, L., Fanelli, M., Torino, F., Monsignori, M., Gasparini, G. 2006a. Trastuzumab in combination with gemcitabine and vinorelbine as second-line therapy for HER-2/neu overexpress-ing metastatic breast cancer. Oncol. Rep. 16: 393–398
Morabito, A., De Maio, E., Di Maio, M., Normanno, N., and Perrone, F. 2006b. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions. Oncologist 11: 753–764
Nabholtz, J.M., Senn, H.J., Bezwoda, W.R., Melnychuk, D., Deschênes, L., Douma, J., Vandenberg, T.A., Rapoport, B., Rosso, R., Trillet-Lenoir, V. , Drbal, J., Molino, A., Nortier, J.W.R., Richel, D. J., Nagykalnai, T., Siedlecki, P., Wilking, N., Genot, J.Y., Hupperets, P.S.G.J., Pannuti, F., Skarlos, D., Tomiak, E.M., Murawsky, M., Alakl, M., Riva, A., and Aapro, M. The 304 Study Group. 1999. Prospective randomized trial of docetaxel versus mitomy-cin plus vinblastine in patients with meta-static breast cancer progressing despite previous anthracycline-containing chemotherapy. J. Clin. Oncol. 17: 1413–1424
O'Shaughnessy, J., Miles, D., Vukelja, S., Moiseyenko, V., Ayoub, J.P., Cervantes, G., Fumoleau, P., Jones, S., Lui, W.Y, Mauriac, L., Twelves, C., Van Hazel, G., Verma, S., and Leonard, R. 2002. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J. Clin. Oncol. 20: 2812–2823
O'Shaughnessy, J.A., Vukelja, S., Marsland, T., Kimmel, G., Ratnam, S., and Pippen, J.E. 2004. Phase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancer. Clin. Breast Cancer 5: 142–147
Osoba, D., Slamon, D.J., Burhmore, M., and Murphy, M. 2002. Effects on quality of life of combined trastuzumab and chemotherapy in women with metastatic breast cancer. J. Clin. Oncol. 20: 3106–3113
Pacilio, C., Morabito, A., Nuzzo, F., Gravina, A., Labonia, V. , Landi, G., Rossi, E., De Maio, E., Di Maio, M., D'Aiuto, G., Botti, G., Normanno, N., Chiodini, P., Gallo, C., Perrone, F., and de Matteis, A. on behalf of the NCI-Naples Breast Cancer Group. 2006. Is epirubicin effective in first line chemotherapy of metastatic breast cancer (MBC) after an epirubicin-containing adjuvant treatment? A single centre phase III trial. Br. J. Cancer 94: 1233–1236
Pegram, M.D., Lipton, A., Hayes, D.F., Weber, B.L., Baselga, J.M., Tripathy, D., Baly, D., Baughman, S.A., Twaddel, T., Glaspy, J.A., and Slamon, D.J. 1998. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185 HER2/neu monoclonal antibody plus cisplatin in patients with HER2/ neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J. Clin. Oncol. 16: 2659–2671
Pegram, M.D., Pienkowski, T., Northfelt, D.W., Eiermann, W., Patel, R., Fumoleau, P., Quan, E., Crown, J., Toppmeyer, D., Smylie, M., Riva, A., Blitz, S., Press, M.F., Reese, D., Lindsay, M.A., and Slamon, D.J. 2004. Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-posi-tive advanced breast cancer. J. Natl. Cancer Inst. 96: 759–769
Perez, E.A., Suman, V.J., Rowland, K.M., Ingle, J.N., Salim, M.C.L., Flynn, P.J., Mailliard, J.A., Kardinal, C.G. Krook, J.E., Thrower, A.R., Visscher, D.W., and Jenkins, R.B. 2005. Two concurrent phase II trials of paclitaxel/carbo-platin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin. Breast Cancer 6: 425–432
Pierga, J.Y., Asselain, B., Jouve, M., Diéras, V. , Carton, M., Laurence, V., Girre, V., Beuzeboc, P., Palangié, T., Dorval, T., and Pouillart, P. 2001. Effect of adjuvant chemotherapy on outcome in patients with metastatic breast carcinoma treated with first-line doxorubicin-containing chemotherapy. Cancer 91: 1079–1089
Robert, N., Leyland-Jones, B., Asmar, L., Belt, R., Ilegbodu, D., Loesch, D., Raju, R., Valentine, E., Sayre, R., Cobleigh, M., Albain, K., McCullough, C., Fuchs, L., and Slamon, D.J. 2006. Randomized phase III study of trastu-zumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2—overexpressing metastatic breast cancer. J. Clin. Oncol. 24: 2786–2792
Seidman, A., Hudis, C., Pierri, M.K., Shak, S., Paton, V. , Ashby, M., Murphy, M., Stewart, S.J., and Keefe, D. 2002. Cardiac dysfunction in the trastuzumab clinical trials experience. J. Clin. Oncol. 20: 1215–1221
Sjöström, J., Blomqvist, C., Mourisden, H., Pluzanska, A,. Ottosson-Lönn, S., Bengtsson, N.O., Ostenstad, B., Mjaaland, I., Palm-Sjövall, M., Wist, E., Valvere, V., Anderson, H., and Bergh, J. 1999. Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: A randomised phase III study with crossover on progression by the Scandinavian Breast Group. Eur. J. Cancer 35: 1194–1200
Slamon, D.J., Leyland-Jones, B., Shak, S., Fuchs, H., Paton, V., Bajamonde, A., Fleming, T., Eiermann, W., Wolter, J., Pegram, M., Baselga, J., and Norton, L. 2001. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344: 783–792
Soto, C., Torrecillas, S., Reyes, S., Ramirez, M., Perez, L., Cervantes, G., Gonzalez, F., Tellez, E., Cortes, P., and Benitez. H. 2006. Capecitabine (X) and taxanes in patients (pts) with anthracy-cline-pretreated metastatic breast cancer (MBC): sequential vs.combined therapy results from a MOSG randomized phase III trial. J. Clin. Oncol. 24: 18 S (Abstr. 570)
Stemmler, H.J., Kahlert, S., Brudler, O., Beha, M., Muller, S., Stauch, B., Heinemann, V. 2005. High efficacy of gemcitabine and cisplatin plus trastuzumab in patients with HER2-overexpress-ing metastatic breast cancer: a phase II study. Clin. Oncol. 17: 630–635
Theodoulou, M., Campos, S.M., Batist, G., Winer, E., Norton, L., Hudis, C., and Welles, L. 2002. TLC D99 (D, Myocet) and Herceptin (H) is safe in advanced breast cancer (ABC): final cardiac safety and efficacy analysis. J. Clin. Oncol. 21: (Abstr.216)
Untch, M., Himsl, I., Kahlert, S., Lueck, H.J., Eidtmann, H., Du Bois, A., Meerpohl, H.G., Thomssen, C., Harbeck, N., Jackisch, C., Kreienberg, R., Emons, G., Wallwiener, D., Wiese, W., Schaller, G., Kuhn, W., Muscholl, M., Pauschinger, M., and Langer, B. 2004. Anthracycline and trastuzumab in breast cancer treatment. Oncology 18: 59–64
Vahdat, L.T., Thomas, E., Li R., Jassem, J., Gomez, H., Chung, H., Peck, R., Mukhopadhyay, P., Klimovsky, J., and Roché, H. 2007. Phase III trial of ixabepilone plus capecitabine compared to capecitabine alone in patients with metastatic breast cancer (MBC) previously treated or resistant to an anthracycline and resistant to taxanes. J. Clin. Oncol. 25: 18 S (Abstr. 1006)
Venturini, M., Bruzzi, P., Del Mastro, L., Garrone, O., Bertelli, G., Guelfi, M., Pastorino, S., Rosso, R. and Sertoli, M.R. 1996. Effect of adjuvant chemotherapy with or without anthracyclines on the activity and efficacy of first-line cyclo-phosphamide, epidoxorubicin, and fluorouracil in patients with metastatic breast cancer. J. Clin. Oncol. 14: 764–773
Venturini, M., Bighin, C., Monfardini, S., Cappuzzo, F., Olmeo, N., Durando, A., Puglisi, F., Nicoletto, O., Lambiase, A., and Del Mastro, L. 2006. Multicenter phase II study of trastuzumab in combination with epirubicin and docetaxel as first-line treatment for HER2-overexpressing metastatic breast cancer. Breast Cancer Res. Treat. 95: 45–53
Welt, A., von Minckwitz, G., Oberhoff, C., Borquez, D., Schleucher, R., Loibl, S., Harstrick, A., Kaufmann, M., Seeber, S., and Vanhoefer, U. 2005. Phase I/II study of capecitabine and vinorelbine in pretreated patients with metastatic breast cancer. Ann. Oncol. 16: 64–69
Yamamoto, D., Iwase, S., Kitamura, K., Odagiri, H.. Yamamoto, C., and Nagumo, Y.A. 2008. Phase II study of trastuzumab and capecit-abine for patients with HER2-overexpressing metastatic breast cancer: Japan Breast Cancer Research Network (JBCRN) 00 Trial. Cancer Chemother. Pharmacol. 61: 509–514
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Morabito, A. et al. (2008). Chemotherapy for Metastatic Breast Cancer Patients Who Received Adjuvant Anthracyclines (An Overview). In: Hayat, M.A. (eds) Methods of Cancer Diagnosis, Therapy and Prognosis. Methods of Cancer Diagnosis, Therapy and Prognosis, vol 1. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-8369-3_29
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