Clinical toxicity

Hematopoetic toxicity

Bone marrow suppression is a common feature of all anthracyclines and is the dose limiting toxicity after bolus dose administration. Myelo- and thrombocy-topenia are most prominent after each treatment course with maximal toxicity after 7-10 days (sometimes delayed) with rapid recovery thereafter. The time to nadir and the recovery are dose dependent. The antiproliferating effect of the anthracyclines depends on the proliferation status of the bone marrow cells as well as of the tumor cells [80, 81]. Quiescent, but potentially proliferating cells are relatively insensitive and can explain the recovery of hematopoesis after anthracycline-induced bone marrow hypoplasia. DNR and IDA are the backbone in the treatment of acute leukemia. The dose used for antileukemic treatment is always a dose which induces full aplasia with a much slower recovery of all hematopoietic cells. The antiproliferating effect on human bone marrow clonogenic cells is independent of the infusion rate. For exerting cyto-toxic effects on these cells, tightly-bound cellular anthracycline levels are necessary. These levels can be reached after rapid bolus injection as well as after long(er)-time infusion [82].

Cardiac toxicity

The cardiac toxicity observed after administrations of anthracyclines is unique in terms of pathology and mechanism. Both acute and chronic cardiac toxicity can be observed. The acute toxicity represents a range of arrhythmias which can include a pericarditis-myocarditis combined with congestive heart failure [83]. This kind of toxicity is rare and not dose dependent. Most of all arrythmias will never be seen because most anthracycline administrations in the in- and out-patient setting are performed without any cardiac monitoring. The arrhythmias are only seldom noticed by the patient and occur within a short period of time after administration without any symptoms. This is not the cardiac toxicity which is generally problematic. Quite different is the cumulative cardiac toxicity which is best documented after repeated bolus doses of DOX 60 mg/m2 every 3 weeks. With this schedule, cardiac toxicity develops as a result of cumulative injury to the myocardium. The pathology of this type of toxicity has been described in detail [84]. With each dose there is a progressive injury to the myocardial tissue that is characterized from grade 0 to grade 3. Grade 0 means no change from normal, grade 1 scanty cells with early myofibrillar loss and/or distended sarcoplasmatic reticulum, grade 2 groups of cells with marked myfibrillar loss and/or cytoplasmatic vac-uolization and grade 3 diffuse cell damage with total loss of contractile elements, organelles and mitochondria, and nuclear degeneration. Figure 5 shows the histomorphological changes after doxorubicin therapy representing grade 3 toxicity.

This pathology is unique to the anthracyclines and allows the pathologist to accurately distinguish this cardiac toxicity from other processes. The clinical risk of congestive heart failure (CHF) is small at total doses below certain thresholds. A 5% risk of developing a symptomatic CHF can be deduced from Figure 6. The cumulative doses are 550 mg/m2 for DOX, 800 mg/m2 for DNR and 900 mg/m2 for EPI [33, 85-88]. For IDA no such data are available. The 5% risk for CHF was estimated within the range 120-240 mg/m2. The above mentioned data were published in the 1970s and 1980s. Figure 6 shows the incidence of CHF related to cumulative anthracycline doses.

The lin-log plot shows in principal similar curves for DOX and EPI but EPI's curve is shifted parallel to higher dose levels which reflects the higher dose necessary to damage the heart to the same degree than after DOX. The slope of the DNR curve is not as steep as those for EPI and DOX.

Results from the 1990s and during the last years have corrected these relative high cumulative doses to lower levels. For EPI a CHF incidence of 14% was described recently at 1,000 mg/m2 [89] and those patients who had received 850 to 1,000 mg/m2 EPI had a risk of CHF that further increased from 11% after 1 year to 20% over a 5 year period [90]. For DOX the CHF incidence levels in adults were also recently corrected. Cardiac events were defined as one of three changes in LVEF values compared with baseline as well as clinical CHF. A retrospective analysis of three trials found a risk of

Figure 5. Left side normal cardiac tissue; right side damaged cardiac tissue after anthracycline treatment.

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