Chemo mit Anthracycline +dexrazoxane

[Hella]

Ich habe Lungenmetastasen nach Brustkrebs.
Diese sollen mit einer Chemo ( siehe Betreff ) behandelt werden.

Gibt es Erkenntnisse, ob durch dexrazoxane
die Wirksamkeit von Anthracyclinen beeinträchtigt wird.

[Prof. Wust]

RE: Chemo mit Anthracycline +dexrazoxane


Wie Sie sehen, hat man noch nicht so viele Erfahrungen mit der Substanz (s. 2 Arbeiten aus 2001). Noch ist man in der Phase I/II Testung. Das Dexrazoxane hat vermutlich einen speziell protektiven Effekt am Herzmuskel. Dann würde es den Effekt von Doxorubicin am Tumor nicht oder kaum beeinflussen. Ganz ausschließen läßt sich Ihre Befürchtung nicht. Vermutlich ist der Vorteil aber größer, da man mehr Dosisspielraum erhält. Bitte fragen Sie die Spezialisten vor Ort. Die müssen doch mit der Susbstanz schon einige Erfahrung haben und die gesamte Literatur fast auswendig kennen.

Anthracycline-induced cardiomyopathy.
AU: Keefe,-D-L
AD: Divisions of Cardiology and Critical Care, Memorial Sloan Kettering Center, New York, NY 10021, USA.
SO: Semin-Oncol. 2001 Aug; 28(4 Suppl 12): 2-7
AB: The highly active chemotherapeutic agents doxorubicin, duanorubicin, idarubicin, epirubicin, and mitoxantrone are also associated with acute, largely reversible cardiotoxic effects and a dose-related cardiomyopathy. This cardiomyopathy is characterized by minimal left ventricular enlargement and global systolic dysfunction, usually with associated mild to moderate mitral insufficiency. Historically, this was characterized by myocardial biopsy and radionuclide angio-graphy. More recently, echocardiography has become the most widely available and cost-efficient tool for diagnosis. The precise mechanism of this toxicity has not been fully defined. However, the maximum tolerated cumulative dose can by increased by reducing peak drug levels and concurrent administration of the iron chelator, dexrazoxane. Because anthracycline-induced cardiomyopathy is largely irreversible and cumulative, prevention is the preferred strategy. Monitoring by assessment of left ventricular function by the most reproducible method available as patients approach potentially toxic doses can substantially reduce toxicity. Stress studies before major procedures such as bone marrow or stem cell transplants may be of benefit. This syndrome responds well to conventional therapy for congestive heart failure with angiotensin-converting enzyme inhibitors, digoxin, and diuretics. The beta-blocker carvedilol is often associated with significant improvement in ejection fraction and symptoms and spironolactone is well tolerated and often of benefit. The long-term outlook of the syndrome is much better than previously reported because of advances in therapy and prevention.


Phase I trial of 96-hour continuous infusion of dexrazoxane in patients with advanced malignan-cies.
AU: Tetef,-M-L; Synold,-T-W; Chow,-W; Leong,-L; Margolin,-K; Morgan,-R; Raschko,-J; Shibata,-S; Somlo,-G; Yen,-Y; Groshen,-S; Johnson,-K; Lenz,-H-J; Gandara,-D; Doroshow,-J-H
AD: Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California 91010, USA.
SO: Clin-Cancer-Res. 2001 Jun; 7(6): 1569-76
AB: Dexrazoxane is a bidentate chelator of divalent cations. Pretreatment with short infusions of dexrazoxane prior to bolus doxorubicin has been shown to lessen the incidence and severity of anthracycline-associated cardiac toxicity. However, because of rapid, diffusion-mediated cellular uptake and the short plasma half-life of dexrazoxane, combined with prolonged cellular retention of doxorubicin, dexrazoxane may be more effective when administered as a continuous infusion. Thus, a Phase I pharmacokinetic trial of a 96-h infusion of dexrazoxane was performed. Dexra-zoxane doses were escalated in cohorts of 3 to 6 patients per dose level. All patients received granulocyte-colony stimulating factor at a dose of 5 microg/kg/day starting 24 h after completion of the dexrazoxane infusion. Plasma samples were collected and analyzed for dexrazoxane by high-performance liquid chromatography. Urine collections were performed at baseline and du-ring the infusion to determine the renal clearance of dexrazoxane and the excretion rate of diva-lent cations. Twenty-two patients were enrolled at doses ranging from 125 to 250 mg/m(2)/day. Grade 3 and 4 toxicities included grade 4 thrombocytopenia in 2 patients treated at 250 mg/m(2)/day, grade 3 thrombocytopenia and grade 4 nausea and vomiting in 1 patient treated at 221 mg/m(2)/day, grade 4 diarrhea and grade 3 nausea and vomiting in 1 patient treated at 221 mg/m(2)/day, and grade 3 hypertension in 1 patient treated at 166.25 mg/m(2)/day. Steady-state dexrazoxane levels ranged from 496 microg/l (2.2 microM) to 1639 microg/l (7.4 microM). Dex-razoxane plasma CL(ss) and elimination t(1/2) were 7.2 +/- 1.6 l/h/m(2) and 2.0 +/- 0.8 h, re-spectively. The mean percentage of administered dexrazoxane recovered in the urine at steady state was 30% (range, 10-66%). Urinary iron and zinc excretion during the dexrazoxane infusion increased in 12 of 18 and 19 of 19 patients by a median of 3.7- and 2.4-fold, respectively. These results suggest that dexrazoxane as a 96-h infusion can be safely administered with granu-locyte-colony stimulating factor at doses that achieve plasma levels that have been demonstrated previously to inhibit topoisomerase II activity and to induce apoptosis in vitro. Additional studies will be required to determine whether the combination of continuous infusions of dexrazoxane and doxorubicin would provide enhanced cardioprotection compared with the currently recommended bolus or short infusion schedules.