Different dosage schedules for reducing cardiotoxicity in cancer patients receiving anthracycline ch

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Different dosage schedules for reducing
cardiotoxicity in cancer patients receiving
anthracycline chemotherapy A Cochrane
Systematic review

• Heleen van der Pal, Elvira van Dalen, Huib Caron,
  Leontien Kremer
• Amsterdam
• The Netherlands

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Objectives

• Primary objective
• To determine the cardiotoxicity of different peak
  doses and different infusion duration of
  anthracycline therapy in patients with cancer.
• Primary outcomes
• Clinical heart failure
• Subclinical cardiac damage

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Methods SR

• Identification and inclusion RCTs
• Quality assessment of included studies
• Data extraction
• Analyses (pooling)
• Summary

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Methods

• Identification of RCTs
• Electronic databases of MEDLINE, EMBASE and
  CENTRAL (June 2004)
• Conference proceedings of SIOP and ASCO (2000-
  2004)
• Reference lists
• Experts in the field
• No language restriction.

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Methods

• Inclusion criteria for studies
• Randomized controlled trial (RCT)
• Comparing the efficacy for reducing heart damage
  of
• different peak dose (but same anthracycline
  derivate and same cumulative dose)
• or
• different infusion duration (but same
  anthracycline derivate and same cumulative dose)
• Patients with any type of cancer
• No age restriction
• Description of clinical and / or subclinical
  heart failure

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Methods search strategy.

• anthracyclines OR anthracyclin OR anthracycline
  antibiotics OR antibiotics, anthracycline OR
  4-demethoxydaunorubicin OR 4 demethoxydaunorubicin
  OR 4-desmethoxydaunorubicin OR 4
  desmethoxydaunorubicin OR IMI 30 OR IMI30 OR
  IMI-30 OR idarubicin hydrochloride OR
  hydrochloride, idarubicin OR NSC 256439 OR
  NSC-256439 OR NSC256439 OR idarubicin OR
  idarubic OR 4'-epiadriamycin OR 4' epiadriamycin
  OR 4'-epidoxorubicin OR 4' epidoxorubicin OR
  4'-epi-doxorubicin OR 4' epi doxorubicin
  4'-epi-adriamycin OR 4' epi adriamycin OR
  4'-epi-DXR OR 4' epi DXR OR epirubicin
  hydrochloride OR hydrochloride, epirubicin OR
  farmorubicin OR IMI-28 OR IMI 28 OR IMI28 OR NSC
  256942 OR NSC-256942 OR NSC256942 OR epirubicin
  OR epirubic OR adriablastine OR adriblastin OR
  adriablastin OR adriamycin OR DOX-SL OR DOX SL OR
  DOXSL OR doxorubicin hydrochloride OR
  hydrochloride doxorubicin OR doxorubic OR
  adriamyc OR dauno-rubidomycine OR dauno
  rubidomycin OR rubidomycin OR rubomycin OR
  daunomycin OR cerubidine OR daunoblastin OR
  daunoblastine OR daunorubicin hydrochloride OR
  hydrochloride, daunorubicin OR daunorubic OR
  rubidomyc OR NSC-82151 OR NSC 82151 OR NSC82151
  OR daunoxome OR daunosom OR doxil OR caelyx OR
  liposomal doxorubicin OR doxorubicin, liposomal.
• administration and dosage OR administration
  schedule, drug OR administration schedules, drug
  OR drug administration schedules OR schedule,
  drug administration OR schedules, drug
  administration OR drug administration schedule OR
  cumulative OR peak OR infusion duration OR
  dosage.
• heart OR heart diseases OR heart disease OR
  disease, heart OR diseases, heart OR cardiac
  diseases OR cardiac disease OR diseases, cardiac
  OR disease, cardiac OR cardiotoxicity OR
  cardiomyopathy OR heart failure, congestive OR
  heart failure OR cardiomyopathy, congestive OR
  ventricular dysfunction OR ventricular
  dysfunction, left OR ventricular dysfunction,
  right.
• Cochrane trial search strategy

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Results
Studies from electronic databases N 2423
Additional studies from bibliography N 5
Excluded N 2388
Additional studies from conference proceedings N
2
42 possible relevant trials
Excluded N 36
6 included RCT
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Results

• 0 RCTs evaluating different peak doses
• (with same anthracycline dose in both arms)
• 6 RCTs evaluating infusion duration
• (with same anthracycline dose in both arms)
• 4 studies in adults / 2 studies in children

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Results

• Clinical heart failure

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Results

• Subclinical cardiac damage
• 3 RCTs with different definitions of subclinical
  heart failure
• Lipshultz Z-score of echocardiographic
  parameters no difference
• Shapira significant difference in mean fall in
  cardiac function between
• bolus group17
• continuous infusion group6
• Steinherz median change in cardiac function
• bolus group-6.5
• continuous infusion group1

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Results

• Tumor response

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Conclusions

• Clinical heart failure
• In adults 4 RCTs RR 0.27 (0.09 to 0.81)
• lower risk for infusion duration 6 hours
  compared to infusion duration
• In children 1 RCT no clinical heart failure 1
  RCT unknown
• Subclinical heart failure
• In adults 1 RCT less fall in cardiac function
  for continuous infusion
• In children 1 RCT no difference 1 RCT less
  fall in cardiac function continuous infusion
• Response rate/ survival
• No statistical significant difference

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Conclusions

• Advice based on current evidence
• If the risk of cardiac damage is expected to be
  high, an infusion duration of anthracyclines of 6
  hours or longer should be considered.

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Results

• Study N of pts Adult/child Tumor
  Anthra.derivate
• Cum.dosis
• Casper 1991 82 adult sarcoma doxo
• median 420
• Hortobagyi1989 52 adult mamma epi
• median 520
• Lipshultz 2002 145 child leukemia doxo
• median 336
• Shapira 1990 62 adult mamma/ doxo
• ovaria median 420
• Steinherz 1993 44 child leukemia dauno
• median 360
• Zalupski 1991 240 adult mamma doxo
• median 240