METHODS

A literature search was conducted on PubMed, Google Scholar, and ClinicalTrials.gov using the following main keywords: liposomal DOX, Doxil® and BC, Caelyx® and BC, and Doxil® or Caelyx® and combinations in BC, to obtain relevant publications evaluating the safety and efficacy of L-DOX in the treatment of breast tumors. Additionally, information regarding the PK and safety profiles of L-DOX and conventional DOX was acquired mainly from drug monographs. Publications assessed in this review included Phases II and III clinical trials of patients with BC, ranging from early to metastatic stages. No particular preference was given in regard to BC subtype, and the only criteria that needed to be met for combinations were the use of L-DOX in at least one arm with at least one additional agent.

RESULTS

Tables 1 and 2 highlight the disparity in PK parameters and toxicity profiles between L-DOX and DOX. These can be attributed to differences in the formulation of the two agents, with the encapsulation of free DOX into a phospholipid bilayer and exterior PEGylation of the liposomes providing improvements in terms of increasing the drug’s half-life (T1/2), decreasing both the volume of distribution (Vd) and plasma CL, and reducing the severity of toxicity associated with the use of anthracyclines. L-DOX’s decreased CL (~ 0.7 vs 324–809 mL/min/m2 for DOX) and increased T1/2 (55±4.8 vs 20–48 h for DOX) may be attributed to decreased metabolism by the liver and MPS. L-DOX liposomes are ~80–90 nm in diameter, although some references state that the size of the molecule is ≥100 nm, a characteristic that impedes their passage across hepatic sinusoidal epithelial fenestrations and decreases their metabolism by hepatocytes. In addition, PEGylation of liposomes decreases their opsonization by immunoglobulin/complement proteins and their uptake by phagocytic cells of the MPS (eg, Kupffer cells and splenic macrophages), thus prolonging the agent’s plasma circulation time.


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Another advantage of L-DOX is its extremely small volume of distribution in comparison to that of DOX (2.72±0.12 vs 809–1,214 L/m2). While DOX’s large Vd indicates that it can effectively distribute into all compartments of the body, its lack of selectivity for tumors means that it can cause a wide range of toxicities. In contrast, the small volume of distribution of L-DOX indicates that the drug is mostly confined into the vascular space, with little free DOX available, as the drug is contained within the liposomes and does not distribute freely to healthy tissues. The small size of L-DOX allows it to extravasate more selectively across fenestrations in the epithelium of blood vessels supplying tumors, where it releases DOX, meaning that generally the use of L-DOX is associated with milder side effects.5,14 The classic adverse effect associated with DOX use is cardiotoxicity that can range in severity from an acute form that develops shortly after exposure to DOX to a more severe late form where patients may experience decreases in left ventricular ejection fraction (LVEF) and a subsequent diagnosis of DOX induced CHF. Furthermore, the use of DOX is limited by a cumulative lifetime dose limit of up to 550 or 450 mg/m2 if a patient received previous mediastinal radiation. In contrast, the more common toxicities from L-DOX use include palmar–plantar erythrodysesthesia, nausea, and alopecia.16,21–25

Since DOX is considered one of the most effective chemotherapy drugs available, it is often added to regimens for localized or metastatic BC as first- or second-line therapy, as a part of a neoadjuvant therapy prior to surgery or as a salvage therapy. Although it is an effective agent, the risks of cardiotoxicity, particularly when combined with other medications associated with the development of CHF, such as trastuzumab and cyclophosphamide, can limit its use.26 In the case of L-DOX, the decreased rates of cardiotoxicity due to the formulation/PK differences described in the preceding paragraph allows its inclusion in regimens where free DOX would have a high risk of cardiotoxicity. Table 3 summarizes several trials where L-DOX has been combined with other chemotherapeutics or targeted therapies. Of note, a study combining L-DOX, trastuzumab, and cyclophosphamide was one of the most effective, with an overall survival of 34.2 months and the progression-free survival (PFS) of 12 months.27 In terms of toxicity, eight of the 48 included patients experienced asymptomatic decreases in LVEF and all but one recovered; of the affected patients, six patients had prior exposure to anthracyclines. As for the other trials included in Table 3, a majority did not find any significant changes to LVEF or high incidences of clinically relevant cardiotoxicity; however, in several instances where mild-to-moderate cardiotoxicity was reported, it was often in patients who either had prior anthracycline exposure or were concurrently being treated with trastuzumab.27–31

DISCUSSION

The decreased risk for the cardiotoxicity of L-DOX combined with its comparable efficacy to DOX in the treatment of BC has made it a suitable alternative therapy in treatment regimens that traditionally utilized conventional DOX.16 In the in vivo setting, the prolonged systemic circulation of L-DOX due to its relatively long half-life,32 along with its selective delivery to the tumor site due to its extravasation through leaky tumor vasculature,33 results in a higher tumor accumulation as compared to normal tissues. In addition, circulating free-drug concentrations in plasma are reduced due to the highly stable L-DOX formulation, leading to lower cardiac tissue exposure of free-DOX, as compared to tumor tissue. Thus, the use of L-DOX would not only be able to alleviate cardiotoxicity but also to retain significant cytotoxic activity against target tumor cells, due to differences in exposure as well as relative potency of DOX in both tissue types. This is in agreement with results from a Phase III study,16 where L-DOX was shown to be as efficacious as DOX, with significantly reduced cardiotoxicity and other adverse events, in patients with metastatic BC.

Table 3 summarizes all clinical trials for combinatorial effects of L-DOX with other chemotherapeutics and targeted agents. It is noted that practically all trials are Phase II, and the cardiotoxic events observed were either very low or not existent. In most cases where patients experienced mild-to-moderate cardiotoxicity, they were reported to have received prior anthracycline therapy or were on regimens that included trastuzumab, which is known to augment cardiotoxicity caused due to DOX.34Nevertheless, the cardiotoxicity observed in the case of L-DOX was significantly lower than that observed with DOX, thus establishing the cardiac safety of this formulation and supporting its clinical use.

In this work, we sought to discuss the therapeutic use of L-DOX in BC. A review of available Phase II and III trials in BC patients has demonstrated that the use of L-DOX generally causes very little cardiotoxicity, while retaining efficacy when used in combination with other chemotherapeutics. Together, this information suggests that L-DOX should continue to be evaluated in further Phase II and III trials in BC, as it remains an effective agent when combined with other chemotherapeutics and is a reasonable agent to substitute in the place of conventional DOX, particularly in patients who are at higher risk for cardiotoxicity.

Disclosure

The authors report no conflicts of interest in this work.


Yesenia L Franco,*Tanaya R Vaidya,* Sihem Ait-Oudhia

Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL, USA

*These authors contributed equally to this work 


References

1. BreastCancer.Org [webpage on the Internet]. U.S Breast Cancer Statisctics. 2016. Available from: http://www.breastcancer.org/symptoms/understand_bc/statistics. Accessed December 11, 2016.

2. Nakada H, Nakagomi H, Hirotsu Y, et al. A study of tumor heterogeneity in a case with breast cancer. Breast Cancer. 2017;24(3):483–489.

3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687–1717.

4. Tacar O, Sriamornsak P, Dass CR. Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J Pharm Pharmacol. 2013;65(2):157–170.

5. Gabizon AA, Patil Y, La-Beck NM. New insights and evolving role of pegylated liposomal doxorubicin in cancer therapy. Drug Resist Updat. 2016;29:90–106.

6. Ott M, Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S. Cytochrome c release from mitochondria proceeds by a two-step process. Proc Natl Acad Sci U S A. 2002;99(3):1259–1263.

7. Shan K, Lincoff AM, Young JB. Anthracycline-induced cardiotoxicity. Ann Intern Med. 1996;125(1):47–58.

8. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97(11):2869–2879.

9. Bria E, Cuppone F, Fornier M, et al. Cardiotoxicity and incidence of brain metastases after adjuvant trastuzumab for early breast cancer: the dark side of the moon? A meta-analysis of the randomized trials. Breast Cancer Res Treat. 2008;109(2):231–239.

10. Lao J, Madani J, Puértolas T, et al. Liposomal doxorubicin in the treatment of breast cancer patients: a review. J Drug Deliv. 2013;2013:456409–456412.

11. Janssen. Caelyx Product Monograph. 2011. Available from: https://www.janssen.com/canada/sites/www_janssen_com_canada/files/prod_files/live/caelyx_cpm.pdf. Accessed August 20, 2018.

12. Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat Rev Cancer. 2006;6(8):583–592.

13. Nichols JW, Bae YH. EPR: evidence and fallacy. J Control Release. 2014;190:451–464.

14. Hilmer SN, Cogger VC, Muller M, Le Couteur DG. The hepatic pharmacokinetics of doxorubicin and liposomal doxorubicin. Drug Metab Dispos. 2004;32(8):794–799.

15. Rivera E. Liposomal anthracyclines in metastatic breast cancer: clinical update. Oncologist. 2003;8(suppl 2):3–9.

16. O’Brien ME, Wigler N, Inbar M, et al; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004;15(3):440–449.

17. Doxil – Dosing for progressed or recurrent ovarian cancer [webpage on the Internet]. Janssen Products, LP; 2018. Available from: https://www.doxil.com/hcp/progressed-or-recurrent-ovarian-cancer/. Accessed August 20, 2018.

18. FDA Approves Supplemental New Drug Application for DOXIL [webpage on the Internet]. Manchester: News Medical Life Sciences; 2009. Available from: http://www.news-medical.net/news/20090910/FDA-approves-Supplemental-New-Drug-Application-for-DOXIL.aspx. Accessed August 20, 2018.

19. Espelin CW, Leonard SC, Geretti E, Wickham TJ, Hendriks BS. Dual HER2 Targeting with trastuzumab and liposomal-encapsulated doxorubicin (MM-302) demonstrates synergistic antitumor activity in breast and gastric cancer. Cancer Res. 2016;76(6):1517–1527.

20. Rafiyath SM, Rasul M, Lee B, Wei G, Lamba G, Liu D. Comparison of safety and toxicity of liposomal doxorubicin vs. conventional anthracyclines: a meta-analysis. Exp Hematol Oncol. 2012;1(1):10.

21. Friberg LE, Karlsson MO. Mechanistic models for myelosuppression. Invest New Drugs. 2003;21(2):183–194.

22. Friberg LE, Hassan SB, Lindhagen E, Larsson R, Karlsson MO. Pharmacokinetic-pharmacodynamic modelling of the schedule-dependent effect of the anti-cancer agent CHS 828 in a rat hollow fibre model. Eur J Pharm Sci. 2005;25(1):163–173.

23. Minami H, Sasaki Y, Saijo N, et al. Indirect-response model for the time course of leukopenia with anticancer drugs. Clin Pharmacol Ther. 1998;64(5):511–521.

24. Friberg LE, Brindley CJ, Karlsson MO, Devlin AJ. Models of schedule dependent haematological toxicity of 2′-deoxy-2′-methylidenecytidine (DMDC). Eur J Clin Pharmacol. 2000;56(8):567–574.

25. Outomuro D, Grana DR, Azzato F, Milei J. Adriamycin-induced myocardial toxicity: new solutions for an old problem? Int J Cardiol. 2007;117(1):6–15.

26. Bovelli D, Plataniotis G, Roila F; ESMO Guidelines Working Group. Cardiotoxicity of chemotherapeutic agents and radiotherapy-related heart disease: ESMO clinical practice guidelines. Ann Oncol. 2010;21(suppl 5):v277–v282.

27. Martín M, Sánchez-Rovira P, Muñoz M, et al; GEICAM. Pegylated liposomal doxorubicin in combination with cyclophosphamide and trastuzumab in HER2-positive metastatic breast cancer patients: efficacy and cardiac safety from the GEICAM/2004-05 study. Ann Oncol. 2011;22(12):2591–2596.

28. Chia S, Clemons M, Martin LA, et al. Pegylated liposomal doxorubicin and trastuzumab in HER-2 overexpressing metastatic breast cancer: a multicenter phase II trial. J Clin Oncol. 2006;24(18):2773–2778.

29. Ardavanis A, Mavroudis D, Kalbakis K, et al. Pegylated liposomal doxorubicin in combination with vinorelbine as salvage treatment in pretreated patients with advanced breast cancer: a multicentre phase II study. Cancer Chemother Pharmacol. 2006;58(6):742–748.

30. Stickeler E, Klar M, Watermann D, et al. Pegylated liposomal doxorubicin and trastuzumab as 1st and 2nd line therapy in her2/neu positive metastatic breast cancer: a multicenter phase II trial. Breast Cancer Res Treat. 2009;117(3):591–598.

31. Torrisi R, Cardillo A, Cancello G, et al. Phase II trial of combination of pegylated liposomal doxorubicin, cisplatin, and infusional 5-fluorouracil (CCF) plus trastuzumab as preoperative treatment for locally advanced and inflammatory breast cancer. Clin Breast Cancer. 2010;10(6):483–488.

32. Gabizon A, Catane R, Uziely B, et al. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res. 1994;54(4):987–992.

33. Soloman R, Gabizon AA. Clinical pharmacology of liposomal anthracyclines: focus on pegylated liposomal doxorubicin. Clin Lymphoma Myeloma. 2008;8(1):21–32.

34. Romond EH, Jeong JH, Rastogi P, et al. Seven-year follow-up assessment of cardiac function in NSABP B-31, a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel (ACP) with ACP plus trastuzumab as adjuvant therapy for patients with node-positive, human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2012;30(31):3792–3799.

35. Doxorubicin full prescribing information [webpage on the internet]. DAILYMED. Available from: https://dailymed.nlm.nih.gov/dailymed/dru gInfo.cfm?setid=1fd148fb-0fbc-4b6f-b790-23546fb46a71#section-11.2. Accessed August 20, 2018.

36. Doxil full prescribing information [webpage on the internet]. DAILYMED. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=21d9c619-7e94-49e2-ac41-31e9ea96554a#section-11.2. Accessed August 20, 2018.

37. Rochlitz C, Ruhstaller T, Lerch S, et al; Swiss Group for Clinical Cancer Research (SAKK). Combination of bevacizumab and 2-weekly pegylated liposomal doxorubicin as first-line therapy for locally recurrent or metastatic breast cancer. A multicenter, single-arm phase II trial (SAKK 24/06). Ann Oncol. 2011;22(1):80–85.

38. Irvin WJ, Orlowski RZ, Chiu WK, et al. Phase II study of bortezomib and pegylated liposomal doxorubicin in the treatment of metastatic breast cancer. Clin Breast Cancer. 2010;10(6):465–470.

39. Collea RP, Kruter FW, Cantrell JE, et al. Pegylated liposomal doxorubicin plus carboplatin in patients with metastatic breast cancer: a phase II study. Ann Oncol. 2012;23(10):2599–2605.

40. Overmoyer B, Silverman P, Holder LW, Tripathy D, Henderson IC. Pegylated liposomal doxorubicin and cyclophosphamide as first-line therapy for patients with metastatic or recurrent breast cancer. Clin Breast Cancer. 2005;6(2):150–157.

41. Kurtz JE, Rousseau F, Meyer N, et al. Phase II trial of pegylated liposomal doxorubicin-cyclophosphamide combination as first-line chemotherapy in older metastatic breast cancer patients. Oncology. 2007;73(3–4):210–214.

42. Rau KM, Lin YC, Chen YY, et al. Pegylated liposomal doxorubicin (Lipo-Dox®) combined with cyclophosphamide and 5-fluorouracil is effective and safe as salvage chemotherapy in taxane-treated metastatic breast cancer: an open-label, multi-center, non-comparative phase II study. BMC Cancer. 2015;15:423.

43. Gil-Gil MJ, Bellet M, Morales S, et al. Pegylated liposomal doxorubicin plus cyclophosphamide followed by paclitaxel as primary chemotherapy in elderly or cardiotoxicity-prone patients with high-risk breast cancer: results of the phase II CAPRICE study. Breast Cancer Res Treat. 2015;151(3):597–606.

44. Tuxen MK, Cold S, Tange UB, Balslev E, Nielsen DL. Phase II study of neoadjuvant pegylated liposomal doxorubicin and cyclophosphamide ± trastuzumab followed by docetaxel in locally advanced breast cancer. Acta Oncol. 2014;53(10):1440–1445.

45. de La Fouchardière C, Largillier R, Goubely Y, et al. Docetaxel and pegylated liposomal doxorubicin combination as first-line therapy for metastatic breast cancer patients: results of the phase II GINECO trial CAPYTTOLE. Ann Oncol. 2009;20(12):1959–1963.

46. Wolff AC, Wang M, Li H, et al. Phase II trial of pegylated liposomal doxorubicin plus docetaxel with and without trastuzumab in metastatic breast cancer: Eastern Cooperative Oncology Group trial E3198. Breast Cancer Res Treat. 2010;121(1):111–120.

47. Sparano JA, Makhson AN, Semiglazov VF, et al. Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized phase III study. J Clin Oncol. 2009;27(27):4522–4529.

48. Fabi A, Ferretti G, Papaldo P, et al. Pegylated liposomal doxorubicin in combination with gemcitabine: a phase II study in anthracycline-naïve and anthracycline pretreated metastatic breast cancer patients. Cancer Chemother Pharmacol. 2006;57(5):615–623.

49. Rivera E, Valero V, Arun B, et al. Phase II study of pegylated liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancer. J Clin Oncol. 2003;21(17):3249–3254.

50. Adamo V, Lorusso V, Rossello R, et al. Pegylated liposomal doxorubicin and gemcitabine in the front-line treatment of recurrent/metastatic breast cancer: a multicentre phase II study. Br J Cancer. 2008;98(12):1916–1921.

51. Artioli G, Grazia A, Mocellin S, et al. Phase II study of neoadjuvant gemcitabine, pegylated liposomal doxorubicin, and docetaxel in locally advanced breast cancer. Anticancer Res. 2010;30(9):3817–3821.

52. Pircher M, Mlineritsch B, Fridrik MA, et al. Lapatinib-plus-pegylated liposomal doxorubicin in advanced HER2-positive breast cancer following trastuzumab: a phase II trial. Anticancer Res. 2015;35(1):517–521.

53. Rossi D, Baldelli AM, Casadei V, et al. Neoadjuvant chemotherapy with low dose of pegylated liposomal doxorubicin plus weekly paclitaxel in operable and locally advanced breast cancer. Anticancer Drugs. 2008;19(7):733–737.

54. Vorobiof DA, Rapoport BL, Chasen MR, et al. First line therapy with paclitaxel (taxol) and pegylated liposomal doxorubicin (caelyx) in patients with metastatic breast cancer: a multicentre phase II study. Breast. 2004;13(3):219–226.

55. Christodoulou C, Kostopoulos I, Kalofonos HP, et al; Study of the Hellenic Cooperative Oncology Group. Trastuzumab combined with pegylated liposomal doxorubicin in patients with metastatic breast cancer. Phase II Study of the Hellenic Cooperative Oncology Group (HeCOG) with biomarker evaluation. Oncology. 2009;76(4):275–285.

56. Chow LW, Yip AY, Lang BH. A phase II trial of vinorelbine and pegylated liposomal doxorubicin in patients with pretreated metastatic breast cancer. Am J Clin Oncol. 2007;30(2):133–138.

57. Martin M, García-Donas J, Casado A, et al. Phase II study of pegylated liposomal doxorubicin plus vinorelbine in breast cancer with previous anthracycline exposure. Clin Breast Cancer. 2004;5(5):353–357.

58. Vici P, Colucci G, Giotta F, et al. A multicenter prospective phase II randomized trial of epirubicin/vinorelbine versus pegylated liposomal doxorubicin/vinorelbine as first-line treatment in advanced breast cancer. A GOIM study. J Exp Clin Cancer Res. 2011;30:39.

Source: Breast Cancer: Targets and Therapy
Originally published September 11, 2018.