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The treatment of malignant disease has to be finely balanced to obtain maximal cure rates at the least possible clinical cost to the patient. Cardiotoxicity can be a consequence of radiation treatment ( Hancock et al, 1993 ; Cameron et al, 1998 ), chemotherapeutic agents and biological response modifiers ( Hochster et al, 1995 ). However, anthracyclines are by far the most important group clinically and this review will focus on methods of reducing anthracycline-induced cardiotoxicity. Anthracyclines are active agents in the treatment armamenterium for both haematological ( Hitchcock-Bryans et al, 1986 ; Lilleyman et al, 1997 ; Johnson et al, 1998 ; Usui et al, 1998 ) and oncological malignancies ( Smith et al, 1991 ; Bonadonna et al, 1996 ), with good evidence of a dose–response relationship.

Dose-limiting cardiotoxicity was observed in early clinical trials ( Lefrak et al, 1973 ), and the risk factors for toxicity are now well elucidated ( Von Hoff et al, 1977 ). Total cumulative dose is the most predictive ( Von Hoff et al, 1979 ; Nysom et al, 1998 ); other factors are dose intensity ( Sorenson et al, 1995 ; Kakadekar et al, 1997 ; Krischer et al, 1998 ), age, both young age and elderly (>70 years) ( Lipshultz et al, 1991 ; von Hoff et al, 1979 ), gender ( Lipshulz et al, 1995 ; Krischer et al, 1998 ), pre-existing heart disease and hypertension ( von Hoff et al, 1979 ), cardiac radiation, and length of follow-up ( Steinhertz et al, 1991 ).

The natural history of anthracycline cardiotoxicity is unclear. Acute toxicity can occur on-treatment or arising within weeks or months of finishing treatment. This may present with heart failure due to dilating cardiomyopathy, abnormalities of cardiac rhythm, or sudden death. Congestive cardiac failure (CCF) can be amenable to medical treatment, and some paediatric patients regain good compensatory cardiac function and can discontinue all anti-failure drugs. Late cardiac dysfunction (4–20 years) has been reported in the paediatric population ( Steinhertz et al, 1991 ; Goorin et al, 1990 ), ranging from subclinical dysfunction ( Lipshultz et al, 1991 ; Sorensen et al, 1995 ) to irreversible failure requiring cardiac transplantation ( Levitt et al, 1996 ). Studies evaluating cardioprotection in the paediatric population must take into account this long latent period.

The mechanism of cardiac damage is probably multifactorial and any hypothesis needs to incorporate the clinical characteristics, such as the escalating effect of increasing cumulative dose, idiosyncratic effects, histological changes, partial early reversibility, and the late progressive pattern ( Boucek, 1998).

Histopathological studies highlight the focal nature of the lesions which include loss of myofibrils, vacuolation within myocyte cytoplasm, focal membrane thickening, swelling of the sarcoplasmic reticulum and the mitochondria, and interstial fibrosis without an inflammatory response ( Billingham et al, 1978 ). Studies of cardiac damage usually use the Billingham scoring system, where the grading (scoring 1–3) depends on the percentage of myoctes which show damage by electron microscopy. Myocyte damage cannot be repaired by increase in myocyte numbers after a postnatal age of 6 months ( Truesdell et al, 1994 ), so the damage is compensated by myocyte hypertrophy. This may explain the sudden expotential fall in function ( Steinhertz et al, 1991 ) that occurs in late cardiotoxicity when the remaining hypertrophied cells can no longer compensate. Remodelling after damage may be prevented by the inhibitory effect of anthracycline on cardiac gene expression, and may also, in part, explain this clinical observation ( Boucek, 1998).

The mechanism by which the heart overcomes myocyte damage makes non-invasive detection of early myocardial damage problematical and a poor predictor of outcome ( Torti et al, 1983 ; Valdivieso et al, 1984 ; Bristow et al, 1981 ). The poor predictability of non-invasive monitoring is a real problem in childhood studies, where long-term cardiac well-being is the ultimate end point. This is particularly so as the majority of childhood cancers can be cured with moderate doses of anthracyclines. This differs from adults, where the treatment objective in many cases is to give escalating doses of anthracyclines without precipitating cardiac failure in the short term. One paediatric study showed that normal fractional shortening measurements taken within 6 months from the end of treatment predicted continued normality in the readings in 88% but that abnormal values remained in 71% of patients at long-term follow-up ( Steinhertz et al, 1991 ). Histopathological changes, both on light and electron microscopy in endomyocardial biopsies, are the only truly reliable method of assessing damage and the changes correlate directly with the total doses received. Ewer et al (1984 ) compared the changes in serial endomyocardial biopsies with ejection fractions calculated from echocardiographic or radioisotope techniques in adults and found no correlation between these methods but good correlation between increasing doses of adriamycin and biopsy grading. Only a few adult studies use this invasive monitoring, so assessing the value of differing cardioprotection methods is difficult.

Pathogenesis

  1. Top of page
  2. Pathogenesis
  3. Pharmacokinetics
  4. Mode of administration and scheduling
  5. Anthracycline analogues
  6. Cardioprotectors
  7. Liposomal anthracyclines
  8. Conclusions
  9. Acknowledgements
  10. References

A number of toxic biochemical changes have been identified which cause significant myocyte damage ( Shan et al, 1996 ). These include cellular toxicity from metabolites, generation of oxygen free radicals ( Basser & Green, 1993), release of vasoactive amines and selective inhibition of cardiac muscle gene expression for α-actin, troponin, myosin light chain 2, and the M isoform of creatine kinase ( Ito et al, 1990 ); impaired calcium homeostasis causing intracellular calcium overload ( Boucek et al, 1987 ; Holmberg & Williams, 1990; Kusuoka et al, 1991 ), disturbance of myocardial adrenergic function, interaction with cell membranes, and effects on nucleic acids.

The free radical mediated damage is probably the most significant action causing cardiotoxicity. Considerable tissue damage is caused, in part by perioxidative injury to intracellular membranes, particularly the mitochondria. The protective enzyme systems such as superoxide dismutase, catalase and selenium-dependent glutathione peroxidase are scanty in cardiac muscle and are 10–30% lower than in the liver. The free oxygen radicals are formed by two processes, firstly by the reduction of the anthracycline molecule from a quinone to a semiquinone free radical ( Davies & Doroshow, 1985). Regeneration of quinone releases an electron which reacts with an oxygen molecule producing the highly active hydroxyl radical. The second method is by the formation of an iron complex which participates in the formation of superoxide and hydroxl radicals from molecular oxygen ( Doroshow & Davies, 1985; Dorr, 1996).

Pharmacokinetics

  1. Top of page
  2. Pathogenesis
  3. Pharmacokinetics
  4. Mode of administration and scheduling
  5. Anthracycline analogues
  6. Cardioprotectors
  7. Liposomal anthracyclines
  8. Conclusions
  9. Acknowledgements
  10. References

Anthracyclines are metabolized to a 13-dihydro derivative which may be more cardiotoxic than the parent compound. Doxorubicinol in vitro is twice as cardiotoxic as doxorubicin and daunorubicinol is 6 times more cardiotoxic than daunorubicin ( Samuels, 1998). The rate at which the parent compounds are metabolized differs. Daunorubicin is more rapidly metabolized than doxorubicin and epirubicin. In mice the area under the cuve (AUC) for doxorubicinol is significantly lower than that of doxorubicin, but the AUC for daunorubicinol is only half that of daunorubicin. Samuels (1998) suggested that after bolus injections doxorubicin contributes to nearly all the cardiotoxicity but daunorubicin only causes 25% of the damage, the remainder is caused by daunorubicinol. This work has not been performed using infusions of anthracyclines, but makes the point that regimens using anthracyclines are not necessarily interchangeable. The use of infusions for all anthracyclines may not be appropriate as there may be an increase of the AUC of a more cardiotoxic metabolite. Marked interpatient variability has also been reported ( Twelves et al, 1991 ; Preisler et al, 1984 ).

The clearance of anthracyclines is mainly through bile, with urinary excretion accounting for 10%. Interestingly, studies with doxorubicin in patients with hepatic dysfunction show no increase in cardiac toxicity but increased mucositis and myelosuppression ( Johnson & Richardson, 1998).

This review will discuss anthracycline cardioprotection under three headings: mode of administration, cardioprotective agents, and the use of liposomal delivery of anthracycline.

Mode of administration and scheduling

  1. Top of page
  2. Pathogenesis
  3. Pharmacokinetics
  4. Mode of administration and scheduling
  5. Anthracycline analogues
  6. Cardioprotectors
  7. Liposomal anthracyclines
  8. Conclusions
  9. Acknowledgements
  10. References

Modifiying scheduling of anthracyclines must take into account the pharmokinetics of the different anthracyclines. In reducing cardiotoxicity, efficacy must not be compromised nor should potentiation of other side-effects cause dose limitation.

The modification of treatment schedules occurred because of the premise that peak plasma anthracycline levels were responsible for the cardiotoxic effect whereas the AUC was related to efficacy ( Roberts, 1987; Speth et al, 1987 ), but Samuels (1998) suggested that the AUC of the metabolites might be important for cardiotoxicity with certain anthracyclines.

The early dosing was by single bolus doses 30–75 mg/m2 with the dose intensity limited by the acute side-effects such as myelosuppression, nausea and mucositis. Simple reduction of dose intensity might reduce the incidence of late cardiotoxicity. Sorensen et al (1995 ) noted dose intensity as a risk factor in children treated for Wilms' tumour when the dose intensity varied between 30 and 40 mg/m2 3–6-weekly. Multivariate analysis of left ventricular end systolic wall stress showed dose intensity as a determinant (P = 0.02). In paediatric malignancies dose intensity reduction may be a realistic option because of the high survival rate using moderate doses.

Split dosing (fractionation) and lengthening infusion times (spreading the load) reduces peak plasma dose levels and lengthens exposure time but maintains the AUC ( Speth et al, 1987 ; Twelves et al, 1991 ; Muller et al, 1993 ). Studies of intracellular concentrations are conflicting. Muller et al (1993 ) showed a 43% peak dose reduction in chronic lymphatic leukaemia cells after a 96 h infusion compared with bolus dose but Speth et al (1987 ) showed that the final cellular concentration in melanoma and leukaemic blasts was similar regardless of the method of administration. They noted a 40% loss of cellular doxorubicin within 1 h of injection in the bolus group compared with minimal loss in the long-term infusion group. Studies on cardiac tissue in the rat and rabbit imply that there is an accumulation of doxorubicin and doxorubicinal after multiple dosing regardless of infusion rates, but peak left ventricular values were lower in the prolonged infusion group, although this was not sustained when the animals were killed at 7 d ( Cusack et al, 1993 ; Boucek, 1998).

Clinical studies show that decreasing the peak plasma levels has a beneficial effect on the incidence and severity of cardiotoxity. Von Hoff's historical review of patients charts revealed a reduction of congestive cardiac failure after doxorubicin from 2.8% to 0.8% when split dosing was used ( Von Hoff et al, 1979 ). Torti et al (1983 ) retrieved endomyocardial biopsy material from patients treated for various malignancies who had either received anthracyclines as bolus or weekly doses of equal dose intensity. Multivariate analysis was used to predict cardiac damage, only the type of schedule was found to be significant and cardiac radiation of borderline significance.They estimated that higher cumulative doses of doxorubicin (168 mg/m2) could be given weekly to achieve the same endomyocardial biopsy score. A randomized multi-agent study was performed in patients treated for non-small round cell lung cancer with the only variable being a weekly schedule of doxorubicin (20 mg/m2) compared with a bolus 3-weekly dosing regimen (60 mg/m2). To study the cardiotoxicity all patients underwent cardiac evaluation; 38% in the single dose group and 26% in the split dose group had endomyocardial biopsy at cumulative doxorubicin doses of 250–300 mg/m2, 450–550 mg/m2 and at every 180 mg/m2 increment thereafter. The overall biopsy score was significantly less in the split dose group, but more patients in the single-dose group had received mediastinal radiation ( Valdivieso et al, 1984 ).

These results were supported by Umsawasdi et al (1989 ), both studies showing no loss in efficacy and less myelosuppression, emesis and alopecia in the split dose regimens. In children, a retrospective study showed no advantage of consecutive daily dose administration (33% of single dose given daily for 3 d) compared with bolus dose every 3 weeks at a mean total dose 324 mg/m2 and 299 mg/m2 respectively. The study overall had an unexplained high incidence of cardiac dysfunction and the groups had disproportionate patient numbers, 96 versus 17 respectively, but nevertheless no difference was detected ( Ewer et al, 1998 ).

A number of clinical studies have shown a significant reduction in early cardiotoxicity with increased infusion times ( Zalupski et al, 1991 ; Hortobagyi et al, 1989 ) ( Table I). Legha et al (1982 ) demonstrated, in a prospective non-randomized study in adult patients receiving high-dose doxorubicin, that long infusion rates of 24–96 h protected for cardiotoxicity and did not affect efficacy. Between total doses of 500 and 800 mg/m2 no patients in the infusion arm showed signs of heart failure compared with 24% in the bolus dose cohort (bolus dose 60 mg/m2). At the same total doses in excess of 800 mg/m2 the longer the infusion rate the lower the incidence of heart failure; a comparison between 24–48 h and 96 h infusion gave incidences of 14% and 9% respectively and these differences were backed by endomyocardial biopsy grades.

Table 1. Table I. Cardioprotection studies of infusional anthracyclines ( Legha et al (1982 ), Hortobagyi et al (1989 ), Casper et al (1991 ), Shapiro et al (1989), Zalupski et al (1991 ), Neglia & Woods (1986)). B, bolus; CE, cardiac events (decrease in LVEF/CCF); CCF, congestive cardiac failure; LVEF, left ventricular ejection fraction; MUGA, multigated radionuclide angiography scan.Thumbnail image of

This early study has been supported by adult randomized studies in poor prognostic groups with infusion times ranging from 6 to 96 h, but cardiac toxicity has been documented only from clinical symptoms or non-invasive assessment in the short term ( Shapiro et al, 1990 ; Zalupski et al, 1991 ; Casper et al, 1991 ). In the U.K. many childhood malignancy treatment regimens incorporate anthracyclines given over 6–48 h. There are no studies in children apart from an observational study on five patients with hepatoblastoma who received total doses of doxorubicin ranging from 130 to 720 mg/m2 by 96 h infusion with no cardiac effects ( Steinhertz et al, 1993 ). Long infusions can produce unpredictable myelosuppression and severe stomatitis. Anti-tumour efficacy for long infusions still has to be proven ( Bielack et al, 1996 ). In vitro experiments have suggested long cellular exposure may lead to an increase in drug resistance ( Hu et al, 1995 ; Chevilland et al, 1992 ).

There are no reports as yet on the effect of varying schedules on late-onset cardiac dysfunction. All the above studies used doxorubicin as the anthracycline. The only data on infusional daunorubicin is a small paediatric study which primarily investigated the use of varying induction protocols on reduction of the leukaemic burden. No abnormal echocardiograms were noted in 18 patients in the infusional group (median daunorubicin dose 400 mg/m2), but 4/18 in the bolus cohort (median dose 360 mg/m2) had abnormal studies ( Steinhertz et al, 1993 ).

Lipshultz et al (1996 ) raised concerns that long infusion times in children may still result in myocyte loss resulting in thinner ventricular walls, causing chronic increase in afterload and late decrease in function.

Anthracycline analogues

  1. Top of page
  2. Pathogenesis
  3. Pharmacokinetics
  4. Mode of administration and scheduling
  5. Anthracycline analogues
  6. Cardioprotectors
  7. Liposomal anthracyclines
  8. Conclusions
  9. Acknowledgements
  10. References

Epirubicin has been shown to be active against a number of tumours with response rates varying between 3% and 82% (Arcamone, 1987). Compared with doxorubicin, epirubicin, mg for mg, is less cardiotoxic. The median dose at which cardiac failure occurs is 1134 mg/m2 compared with 492 mg/m2 of doxorubicin after a bolus dose ( Jain et al, 1985 ). This may be attributed to the more rapid plasma clearance of epirubicin due to a different metabolic pathway ( de Valeriola, 1994).

Ryberg et al (1998 ) studied a group of patients with breast cancer who had never received anthracyclines and showed that, at cumulative epirubicin doses of 900 mg/m2, 4% developed CCF which increased to 15% at doses of 1000 mg/m2. Scheduling a single dose versus day 1 and 8 split dose did not affect the risk of cardiotoxicity but the higher the mean single dose level (i.e. cumulative dose divided by the number of injections), the greater was the risk of CCF.

Arcamone (1987) suggested idarubicin as an active anthracycline for oral use in adult non-lymphoblastic leukaemia. Phase III randomized studies have been carried out in adults with acute myeloid leukaemia and it has been found to be as effective as daunorubicin. The oral formulation may be of use for NHL and myeloma ( Johnson & Richardson, 1998). Idarubicin is thought to be less cardiotoxic at equimyelotoxic doses. In one study, relapsed/new patients with MDS/AML who received idarubicin were assessed for cardiotoxicity. Of 127 patients, four developed clinical CCF and of whom three had received prior treatment with anthracyclines or mitroxantrone, 65 patients were assessed for subclinical cardiac damage and 10 showed abnormalities; four had received prior cardiotoxic drugs. The median dose was 138 mg/m2. In view of the previous treatment, little can be drawn from this study regarding the actual cardiotoxicity except that the effect is synergistic with other cardiotoxic agents ( Anderlini et al, 1995 ).

Cardioprotectors

  1. Top of page
  2. Pathogenesis
  3. Pharmacokinetics
  4. Mode of administration and scheduling
  5. Anthracycline analogues
  6. Cardioprotectors
  7. Liposomal anthracyclines
  8. Conclusions
  9. Acknowledgements
  10. References

The search for agents to be used alongside anthracyclines to provide cardiac protection became a reality when research showed the anti-neoplastic effects may be independent of the cardiotoxic effect. Anthracyclines are intercalating agents which block DNA synthesis and effect repair processes ( Painter, 1978); this is probably a more important antineoplastic effect than free radical production. As reviewed above, oxygen free radicals are thought to be the main contributors to cardiotoxicity. This is supported by the studies on animals showing modification of cardiotoxicity by antioxidants such as N-acetylcysteine (NAC), oxypurinol and selenium ( Hershko et al, 1996 ). Small animal (mice, rats, rabbits) studies with NAC, vitamin E and vitamin A ( Singal et al, 1995 ; Milei et al, 1986 ) showed effectiveness but this was not borne out in larger animals (dogs, swine) who received clinically more relevant anthracycline doses. NAC ( Myers et al, 1983 ) and vitamin E ( Breed et al, 1980 ) have been tested for their clinical specificity in humans and found to be ineffective. Probucol, a lipid-lowering agent and antioxident, has been shown in the rat model to protect against cardiac damage and to maintain efficacy in a mouse tumour model ( Singal et al, 1995 ).

Coenzyme Q10 has shown some benefit in children treated for acute lymphoblastic leukaemia in a small study ( Iarussi et al, 1994 ). Calcium antagonists such as verapamil, propranolol and prenyamine have also been considered ( Milei et al, 1986 ). Work on isolated rat hearts suggested an effect on the acute depressive affect of anthracyclines, but no trial in vivo showed evidence of cardioprotection ( Wickman-Coffelt et al, 1983 ).

Amifostine, an organic thiophosphate, has cytoprotective effects for nephrotoxicity, neurotoxicity and myelosuppression. It is thought to act by scavenging free radicals and to form mixed disulphides to protect normal tissues ( Bukowski, 1999). In vivo and in vitro studies in mice have shown a degree of cardioprotection with doxorubicin and daunorubicin but not with mitroxantrone. No human trials have been conducted ( Dorr, 1996).

More interesting is the work on iron chelators. The theory behind the use of chelating agents is that by depletion of intracellular iron there would be less available to form anthracycline–iron complexes and so reducing free radical formation. The full explanation of the effectivness of chelating agents has not been established.

Herman et al (1972 ) demonstrated the cardioprotective properties of EDTA in isolated dog heart muscle. Subsequently EDTA, desferrioxamine and related compounds, although effective metal chelators in other clinical settings, were not shown to be effective in cardioprotection, which may be due to their poor cell membrane penetration ( Hasinoff et al, 1998 ). At the same time, work was in progress to assess the antitumour activity of an EDTA-related compound (ICRF-159 Razoxane) and the cardioprotective properties were then observed ( Creighton et al, 1969 ).

The more soluble ICRF-187 (dexrazoxane) showed a similar effect and has been the agent used in clinical trials. Initial studies were carried out in rabbits treated with daunorubicin with good effect. The myocardial lesions seen in human hearts were identified in the rabbit hearts in all those treated with daunorubicin alone compared with 33% in those treated with ICRF-187 in addition to daunorubicin. This study was extended to dogs using doxorubicin as the anthracycline and the incidence and severity of myocyte damage was significantly reduced ( Hasinoff et al, 1998 ).

Epirubicin cardiotoxicity has also been shown to be reduced by the use of ICRF-187, but no effect was observed with mitoxantrone. The dosing regimes used in humans were mimicked with encouraging results in swine and dogs ( Herman et al, 1981 , 1983). These studies were terminated at the end of the drug treatment, but studies in rats investigating longer-term protection showed continual preservation of the myocytes.

Randomized clinical studies on adults have been published on patients with advanced breast cancer and a small study of patients with soft tissue sarcoma ( Speyer et al, 1992 ; Venturini et al, 1996 ; Swain et al, 1997 ; Lopez et al, 1998 ). The initial study showed more anthracycline could be given if ICRF-187 was used in combination. Swain et al (1997 ) studied a large number of patients (1008) with advanced breast cancer in a blinded randomized controlled study. Doxorubicin in combination with cyclophosphamide and flurouracil were given at 3-weekly intervals.

The initial study used a ratio of ICRF-187 to doxorubicin of 20:1 with an excess of deaths in the ICRF-187 group; subsequently the ratio was reduced to 10:1. The groups were matched for previous treatment and cardiac risk factors. The hazard ratio for a cardiac event (development of CCF or decline in left ventricular ejection fraction (LVEF) as measured by a multigated radionuclide angiography scan (MUGA) in 534 patients was 2.5 times greater in the placebo group than the the ICRF-187 group. Cardiac events occurred in 31% v 15% respectively with CCF only occurring in 8% and 1%. This was statistically significant in the log-rank test but the significance lessened with the Wilcoxon test; this was due to decreased differences with lower-dose doxorubicin, as the effect of cardioprotection kicks in at doses above 400–500 mg/m2.

Lopez et al (1998 ) also showed this effect with epirubicin doses >960 mg/m2. The tumour response rate was less in the ICRF-187 group (47% v 60%), although overall time to progression and survival was similar. Non-cardiac toxicity analysis demonstrated the greater effect of ICRF-187 on myelosuppression, with a significant difference in grade 3/4 toxicity for neutropenia. At present there are no published trials for haematological malignancies.

The first paper reporting the use of ICRF-187 in the paediatric age group showed cardioprotection in a small number of patients with either refractory or relapsed disease who had previously been exposed to anthracyclines. The ICRF-187 group had no cardiac dysfunction at the end of treatment, as measured by echocardiography after anthracycline doses 600–1150 mg/m2. LVEF in the ICRF-187 group fell by a mean of 1% compared with 11% in the non ICRF-187 group ( Bu'Lock et al, 1993 ). To date, there is one small randomized study which has shown a similar result to the adult studies ( Wexler et al, 1996 ).

The dose and method of administration has not been completely determined. It is apparent that ICRF-187 needs to be given prior to or during anthracycline administration because of its short half life, it is probably not so effective when given prior to long infusions. All the clinical studies use ICRF-187 15–30 min prior to a bolus anthracycline dose. The ratio of ICRF-187 to anthracycline dose varies between studies; effectiveness has been shown with ratios between 1:6 and 1:20 (see Table II). The dose has been shown to be directly related to the degree of myelosuppression ( Hochster et al, 1995 ) and at the 1:20 ratio Swain et al (1997 ) showed excess mortality. More work is needed to find the lowest effective dose.

Table 2. Table II. Cardioprotection studies using IRCF-187 ( Speyer et al (1992 ), Venturini et al (1996 ), Swain et al (1997 ), Lopez et al (1998 ), Bu'Lock et al (1993 ), Wexler et al (1996 ), Schiavetti et al (1997 )). CE, cardiac events; CCF, congestive cardiac failure; LVEF, left ventricular ejection fraction; (B)RC, (blinded) randomized controlled trials; OS, observational study; PS, pilot study; Daun., daunorubicin; Epi., epirubicin; Dox., doxorubicin.Thumbnail image of

There are a number of unanswered questions, particularly in paediatric practice ( Lipshultz, 1996). No large randomized study has shown definite proof of reduced morbidity/mortality. It is essential to know whether ICRF-187 affects the anti-tumour effect of anthracyclines. The effectiveness at low anthracycline doses and against the development of late cardiotoxicity in children has not been proven. ICRF has been shown to be involved in the inhibition of topoisomerase II and so theoretically may add to the risk of second malignant neoplasm ( Tanabe et al, 1991 ). To address these issues a large multicentre study needs to be performed with a commitment to long-term outcome.

Liposomal anthracyclines

  1. Top of page
  2. Pathogenesis
  3. Pharmacokinetics
  4. Mode of administration and scheduling
  5. Anthracycline analogues
  6. Cardioprotectors
  7. Liposomal anthracyclines
  8. Conclusions
  9. Acknowledgements
  10. References

The development of particulate drug delivery systems is a theoretically attractive concept of enabling drugs to be delivered to the target tissue and reducing exposure to sensitive organs. Packaging of chemotherapeutic agents may increase tumour dose with reduction of toxicity.

The use of liposomes for drug delivery was first developed 30 years ago and has been extensively investigated, but only recently have products reached the clinical trial stage. Liposomes are diverse and can carry both water or lipid soluble drugs ( Allen, 1998). Their properties are dependent on vesicle size and the composition of the lipid bilayer. The main problems have been associated with the preferential uptake of liposomes by the reticuloendothial system and thus poor availablity of the drug to the target tissue. Manipulation of the lipid bilayer has resulted in the formulation of long circulating liposomes more resistant to macrophage uptake. Two types of anthracycline-containing liposomes have been studied in animal models and humans, one which incorporates polyethylene-glycol (PEG-coated) on to the bilayer and doxorubicin as the encapsulated drug (Doxil) and another using neutral liposomes with high cholesterol content containing daunorubicin (DaunoXome) ( Vaage et al, 1998 ; Forssen & Profitt, 1998).

The uptake in solid tumours is reliant on a liposomal size of <100 nm, liposomal concentration, and abnormal microcirculation with increased capillary permeability in the tumours ( Gabizon, 1994). Stability and drug release in tumours and organs has been studied using radiolabelling with 111Indium ( Presant et al, 1988 ; Patel et al, 1985 ). Work was performed on patients with Kaposi's sarcoma (KS) and it was observed that the liposome uptake was higher than in other tumours ( Presant et al, 1990 ). KS lesions showed significant angiogenesis with thin-walled leaky capillaries ( Wu et al, 1993 ).

Efficacy has been demonstrated for KS with partial response rates of 25–65% with daunorubicin and 80% with encapsulated doxorubicin ( Harrison et al, 1995 ; Gill et al, 1995 ; Tulpule et al, 1998 ; Northfelt et al, 1998 ). Phase I/II trials on adult solid tumours have shown some objective response in breast, advanced ovarian, prostate, head and neck carcinomas, and poor-prognosis lymphoma ( Uziely et al, 1995 ; Gabizon & Muggia, 1998; McBride et al, 1997 ).

Cardiac muscle has a relative lack of macrophages and has an intact capillary system, so with the slow release properties of liposomal-entrapped anthracyclines their use should reduce cardiotoxicity. Studies on rodents, rabbits and dogs have verified this ( Vaage et al, 1998 ). Clinical studies on patients with KS have not reported significant cardiotoxicity up to cumulative doses of liposomal daunorubicin to 1000 mg/m2 ( Gill et al, 1995 ). In a phase I study of liposomal doxorubicin in 56 adults with a range of tumour types, 17 of whom had received >450 mg/m2, there were no cases of clinical heart failure. Monitoring in those patients receiving >240 mg/m2 showed one case of decreased left ventricular ejection fraction (>10% of baseline) ( Uziely et al, 1995 ). There are no published studies in children; however, a phase II study is in progress in Europe on patients in first relapse from a variety of tumours. There are no studies looking at late onset cardiac dysfunction. The dose-limiting toxicites are myelosuppression, severe mucositis with ulceration, and palmar-plantar erythrodysesthesia ( Gordon et al, 1995 ). The hand–foot syndrome is principally seen when using DOX-SL and is related to long half-life; reducing the frequency of doses reduces the incidence ( Gabizon et al, 1998 ).

At present, liposomal anthracycline is not used for haematological malignancies or the destruction of malignant cells in circulation. Further improvement of targeting may be achieved by the attachment of ligands specific for particular tumour cell surfaces. Work is in progress on animal models, for example SCID mice with human B-cell lymphoma using sterically stabilized liposomes with an antibody (anti-CD19) attached to the phospholipid bilayer containing doxorubicin ( Allen, 1998).

Conclusions

  1. Top of page
  2. Pathogenesis
  3. Pharmacokinetics
  4. Mode of administration and scheduling
  5. Anthracycline analogues
  6. Cardioprotectors
  7. Liposomal anthracyclines
  8. Conclusions
  9. Acknowledgements
  10. References

While anthracyclines are important chemotherapeutic drugs, the need for effective cardioprotection is necessary. Long-term morbidity and mortality may increase due to anthracycline cardiac damage in patients who have survived their malignancy. Already, young people are being restricted in their occupational choice if they have received anthracyclines, for fear of cardiac complications. This review highlights the paucity of data on cardioprotection for haematological and paediatric malignancies. Clinical research with adequate numbers of patients needs to be performed in randomized controlled trials, particularly in patient groups with good outcomes so longer-term morbidity/mortality can be assessed. Trials will need to be conducted with the different anthracyclines as results cannot necessarily be translated between drugs. Effective non-invasive methods of comparing cardiac damage at the time of administration which will correlate with late outcome need to be developed so that the inherent lag time required for paediatric studies can be bypassed. The pharmaceutical companies need to take up the challenge to develop cardioprotectors or anthracyclines with less cardiotoxity and similar efficacy.

References

  1. Top of page
  2. Pathogenesis
  3. Pharmacokinetics
  4. Mode of administration and scheduling
  5. Anthracycline analogues
  6. Cardioprotectors
  7. Liposomal anthracyclines
  8. Conclusions
  9. Acknowledgements
  10. References
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