Anthracyclines are a class of chemotherapy drugs that act as topoisomerase II inhibitors. Doxorubicin and daunorubicin were the first anthracyclines developed in the 1960s from bacteria. They intercalate DNA, inhibit topoisomerase and DNA synthesis, and generate free radicals causing DNA damage. Chronic cardiotoxicity is the main toxicity, with risk increasing with cumulative dose. Liposomal doxorubicin and mitoxantrone have less cardiotoxicity. Anthracyclines are used to treat many cancers but dose adjustments are needed for hepatic or renal dysfunction.

1. ANTHRACYCLINES
Dr. Chinmayee Agrawal
Moderator: Dr. Nalini Kilara
25.01.2021
References Used:
1. DeVita, Hellman, and Rosenbergs Cancer Principles
and Practice of Oncology – 11th Edition
2. Physicians Cancer Chemotherapy Manual 2019-Edward
Chu, Vincent Devita
3. UptoDate
4. Ann Oncol 2002

2. OVERVIEW
 History
 Introduction to Topoisomerase Enzyme
 Derivatives of Anthracyclines
 Mechanism of action
 Mechanism of Resistance
 Indication and Dosage
 Regimens
 Toxicity profile

3. HISTORY
 In 1960s, simultaneous efforts by French and Italian
researchers led to the development of Daunorubicin and
Doxorubicin
 Daunorubicin & Doxorubicin- 1st anthracycline
developed
 Formed by fermentation products of bacterium
Streptomyces peucetius var. caesius
 Originally described as antitumor activity.
 Classified as TOPOISOMERASE II INHIBITORS

4. TOPOISOMERASE ENZYME
 DNA Topoisomerase- Enzymes altering topology of
DNA.
 Prevent and resolve DNA and RNA entanglements
and resolve DNA supercoiling during Transcription
and Replication
 2 classes of Topoisomerases: Topoisomerase I
Topoisomerase II

5. TOPOISOMERASE I
 Untwisting the DNA Duplex
Enzyme associated single strand break
Allows broken strand to rotate around the intact
strand
DNA supercoiling is dissipated

6. TOPOISOMERASE II
Double or single stranded DNA pass through
cleavage complex
Intact DNA duplex through the DNA double strand
break generated by enzymes
Top 2 relegates the broken duplex
Such reactions permit DNA decatenation, unknotting
and relaxation of supercoils

7. MECHANISM OF ACTION OF TOPOISOMERASE ENZYME

8. TOPOISOMERASE II INHIBITORS
Acts as interfacial inhibitors by binding at Topoisomerase
DNA interface
Trapping Topoisomerase cleavage complexes
Relegation of cleavage complex depends on structure of
ends of broken DNA
Binding of drug at enzyme DNA interface
Misaligns ends of DNA and precludes Relegation
Stabilization of Topoisomerase cleavage complexes

9. MECHANISM OF ACTION OF TOPOISOMERASE INHIBITORS

10. (B) Intercalates into DNA
Inhibition of DNA synthesis and function
(C) Inhibition of transcription through Inhibition of
DNA dependent RNA Polymerase

11. (D) Formation of cytotoxic oxygen free radicals
Single or double stranded DNA breaks
Subsequent inhibition of DNA synthesis and function
 Cell cycle non specific
(Predominant action on G2/S phase of cell cycle)

12. DERIVATIVES OF CLINICAL USE
ANTHRACYCLINE
 Doxorubicin
 Liposomal Doxorubicin
 Epirubicin
 Idarubicin
 Daunorubicin
ANTHRACENEDIONE
 Mitoxantrone

13. MECHANISM OF DRUG RESISTANCE
 Resistance to topoisomerase targeting drugs can
involve alterations in
Increased expression of the multidrug resistant
(MDR) gene with elevated P-170 levels leading to
drug efflux
Drug accumulation
 Decreased expression of Topoisomerase II.
 Mutation in Topoisomerase II with decreased binding
affinity to drug
 Increased expression of sulphydryl proteins including
glutathione and dependent proteins

14. DRUG DAUNORUBICIN
Powder form
20mg
DOXORUBICIN
Liquid form
10mg, 50mg
EPIRUBICIN
Powder or Liquid
10mg , 50mg,
100mg
IDARUBICIN
Powder
5mg
Plasma Protein
Binding
60-70% 60-70% 80% >90%
CSF/Plasma
Ratio
Very Low Very Low Very Low Very Low
Excretion Biliary (40-50%)
Renal (<10%)
Biliary (50%)
Renal (<10%)
Biliary (60-70%)
Renal (<20%)
Mainly by liver
Renal (15%)
Toxicity Myelosuppression
Mucositis
Alopecia
Cardiac toxicity
Vesicant
Myelosuppression
Mucositis
Alopecia
Cardiac toxicity
Vesicant
Leukopenia
Thrombocytopenia
Cardiotoxicity
Leukopenia
Thrombocytopenia
Cardiotoxicity
Routes of
Administration
Intravenous Intravenous Intravenous Intravenous

15. SOLID TUMOR INDICATIONS OF DOXORUBICIN
 Breast cancer
 Gastric cancer
 Ewing’s sarcoma
 Prostate cancer
 Thyroid cancer
 Nephroblastoma
 Neuroblastoma
 Non small cell lung cancer
 Ovarian cancer
 Transitional cell Bladder ca
 Cervical cancer
 Kaposi Sarcoma

16. HEMATOLOGICAL INDICATIONS
 ALL
 AML
 CLL
 Hodgkin Lymphoma
 Non Hodgkin’s Lymphoma
 Mantle cell Lymphoma
 Mycosis fungoides
 Langerhans cell
 Multiple myeloma

17. DOSE AND DOSE ADJUSTMENT
USUAL DOSE
 Single agent: 60-75 mg/m2 every 3 weeks
15-20 mg/m2 weekly
 Combination therapy: 45-60mg/m2 every 3 weeks
 Continous infusion: 60-90mg/m2 iv over 96 hrs
DOSE ADJUSTMENT
Hepatic dysfunction
 Elevated plasma bilirubin :
50% reduction: 1.2-3.0 mg/dl
75% reduction: 3.1-5.0 mg/dl
With-held: >5mg/dl

18. COMMON REGIMENS
1. AC Regimen
Doxorubicin: 60mg/m2 i.v. on Day1
Cyclophophamide: 600mg/m2 i.v. on D1
x 3 weekly
2. VAC/IE Regimen
Vincristine: 2mg i.v. on Day1
Doxorubicin: 75mg/m2 i.v. on Day1
Cyclophophamide: 1200mg/m2 i.v. on D1
Ifosfamide: 1800mg/m2 i.v. D1-5
Etoposide: 100mg/m2 i.v. D1-5
x 3 weekly

19. 3. ABVD Regimen:
Doxorubicin: 25mg/m2 i.v. on Days1 and 15
Bleomycin: 10U/m2 i.v on Days1 and 15
Vinblastine: 6mg/m2 i.v. on Days1 and 15
Dacarbazzine: 375mg/m2 i.v. in Days1 and 15
x 28 days
4. CHOP Regimen:
Cyclophosphamide: 750mg/m2 i.v. on Day1
Doxorubicin: 50mg/m2 i.v. on Day1
Vincristine: 1.4mg/m2 i.v. on Day1 (Max-2mg)
Prednisone: 100mg/day PO on days 1-5
x 21 days

20. CONTINOUS REGIMEN
5. VAD REGIMEN
Vincristine: 0.4mg/day i.v. continuous infusion on
days 1-4
Doxorubicin: 9mg/m2/day i.v. continuous infusion on
days 1-4
Dexamethasone: 40mg PO on days 1-4, 9-12 and 17-
20
x 28 days

21. CONTINOUS REGIMENS
6. MAID Regimen (Soft Tissue Sarcoma):
Mesna: 2500mg/m2/day i.v. continuous infusion on
Days1-4
Doxorubicin: 20mg/m2/day i.v continuous infusion on
days 1-3
Ifosfamide: 2500mg/m2/day i.v. continuous infusion
on days 1-3
Dacarbazine: 300mg/m2/day i.v. continuous infusion
on days 1-3
x 3 weekly

22. 7. Dose Dense AC Regimen (TNBC or Advanced
Breast Cancer):
Doxorubicin: 60mg/m2 i.v. on Day1
Cyclophophamide: 600mg/m2 i.v. on D1
x 2 weekly

23. DAUNORUBICIN
INDICATION AND USUAL DOSE
 Dose: 30-45mg/m2 per day on 3 consecutive days
in combination chemotherapy
 Single agent- 40mg/m2 every 2 weeks
 Typically administered as i.v push over 3-5min
 ALL: 25mg/m2 i.v in combination with vincristine
and prednisone
 AML: 60-90mg/m2 i.v for 3 consecutive days

24. DOSE ADJUSTMENT
Renal and Hepatic Dysfunction
 50% Dose reduction for either S. Creat or Bilirubin
levels >3mg/dl
 25% Dose reduction : 1.2-2.0 mg/dl

25. EPIRUBICIN
INDICATIONS AND USUAL DOSE
 Breast
 Metastatic Breast cancer
 Gastric cancer
 Dose: 100-120mg/m2 every 3 weeks
DOSE ADJUSTMENTS
Hepatic or renal Dysfunction

26. COMMON REGIMENS
1. EC Regimen
Epirubicin: 100mg/m2 i.v. on Day1
Cyclophophamide: 600mg/m2 i.v. on D1
x 3 weekly
2. FEC Regimen
5-FU: 500mg/m2 i.v. on Day1
Epirubicin: 100mg/m2 i.v. on Day1
Cyclophophamide: 500mg/m2 i.v. on D1
x 3 weekly

27. 3. ECF Regimen
Epirubicin: 50mg/m2 i.v. on Day1
Cisplatin: 60mg/m2 i.v. on D1
5-FU: 200mg/m2 i.v. on Day1
x 3 weekly

28. IDARUBICIN
INDICATIONS AND USUAL DOSAGE
 AML
 ALL
 Chronic myelogenous leukemia in Blast crisis
 Myelodysplastic syndromes
 Dose :12 mg/m2 daily for 3 days in combination
with cytarabine

29. DOSE ADJUSTMENTS
 Hepatic Dysfunction
 Serum Bilirubin: 2.6-5mg/dl: 50% Dose reduction
 >5mg/dl : should not be given
PERCEIVED BENEFIT OF IDARUBICIN
 Can be given in patients with renal impairment

30. LIPOSOMAL DOXORUBICIN
 Liquid form; 20mg & 50mg
 Polyethylene glycol (PEG)ylated liposomal form
which allows for enhancement of drug delivery
 Protected from chemical and enzymatic
degradation, reduced plasma protein binding and
decreased uptake in normal tissues.
 Penetrates tumor tissue into which doxorubicin is
released

31. LIPOSOMAL DOXORUBICIN
INDICATION AND USUAL DOSE
 Kaposi sarcoma- 20mg/m2 every 3 weeks
 Ovarian cancer- 50mg/m2 every 4 weeks
 Multiple Myeloma- 30mg/m2 i.v in combination with
Bortezomib on Days 1,4,8 and 11 every 3 weeks
DOSE ADJUSTMENTS
 Hepatic dysfunction

32. ANTHRACENEDIONES
MITOXANTRONE:
 Only clinically approved
 20mg, Liquid form
 Less cardiotoxic owing to a decreased ability to
undergo oxidation reaction and form free radicals
 Rapidly cleared from plasma and is highly
concentrated in tissues

33. MITOXANTRONE
Indications:
 CRPC: 12-14mg/m2 every 3 weeks
 AML: 12mg/m2 in combination with cytosine
arabinoside for 3 days in treatment of multiple
myeloma
DOSE ADJUSTMENTS:
 Hepatic dysfunction

34. IMPORTANT DRUG
INTERACTION

35. DAUNORUBICIN DOXORUBICIN EPIRUBICIN IDARUBICIN
Dexa and Heparin:
concurrent use
precipitate formation
Dexa, 5FU, Heparin:
concurrent use
precipitate formation
Heparin: concurrent
use precipitate
formation
Heparin: concurrent
use precipitate
formation
Cyclophosphamide :
Hemorrhagic cystitis
and Cardiotoxicity
5FU and
Cyclophosphamide:
Increased
myelosuppression
Probenecid: Increased
risk of uric acid
nephropathy
Phenytoin,
Phenobarbital:
Increased clearance
Cimetidine:
Decreased AUC by
50%
6MP- Increased
hepatotoxicity

36. TOXICITY PROFILE

37. CARDIOTOXICITY
 Common side effects in all anthracyclines
 Chronic cardiotoxicity is the most common type of
anthracycline damage
 Prevalence of late subclinical cardiac damage has
been reported to be more than 57% at a median of
6.4 years after treatment among survivors of
childhood cancers
 The incidence of clinical heart failure as high as
16%, 0.9 to 4.8 years after treatment

38. CLINICAL FEATURES: DIVIDED INTO
A. Acute or subacute : Heart damage that develops
immediately after the infusion of the drug or within a
week of therapy.
B. Early Onset chronic progressive cardiotoxicity:
Depression of myocardial function which occurs during
the treatment or within the first year after treatment
C. Late Onset chronic progressive cardiotoxicity: Occurs
at least 1 year after the end of treatment
Acute: Reversible; Chronic: Irreversible

39. EARLY CARDIOTOXICITY
 Myocarditis
 Pericarditis
 Non ischemic Cardiomyopathy with or without
concomitant arrythmias
 Related to myocyte damage or death resulting in
depressed left ventricular contractility

40. CHRONIC CARDIOTOXICITY
 Cardiomyopathy-
- Myofibrillar loss
- Vacuolar degeneration
- Coalescence of sarcotubular system related
to myocyte damage or death
- Depressed left ventricular contractility -
Decreased left ventricular systolic function
Chronic cardiotoxicity peaks at 1 to 3 months, but can
occur over years after therapy

41. CARDIAC TOXICITY
(A)Electron transfer from Semiquinone to quinone
Direct generation of Reactive oxygen species
Myocardial Damage
(B)Poisoning of Top2B cleavage complexes in
myocardiocytes

42. (C)Doxorubicin accumulates in chromatin and
mitochondria
Reactive oxygen species
Drug mediated inactivation of oxidative
phosphorylation
Mitochondrial damage

44. INVESTIGATIONS:
 Serial LVEFs studies
 Multigated radionucleotide imaging
 2-Dimensional Trans-thoracic ECHO
 Cardiac MRI
 Serologic Methods:
Levels natriuretic peptide
Cardiac Troponin levels

45.  ECG Changes:
Sinus Tachycardia
Low Voltage
Poor R wave Progression
Non specific T wave changes
 Endocardial Biopsy: (Historically)
Loss of myofibrils
Distention of sarcoplasmic reticulum
Vacuolization of cytoplasm
Stellate scars
Adria cells

46. PREDISPOSITION TO CARDIAC DAMAGE
 Previous history of heart disease
 Hypertension
 Mediastinal radiation
 Age <15 yrs or >70 yrs
 Deficiency of HFE gene
 Prior use of anthracyclines or other cardiac toxins
 Co- administration of other chemotherapy like
Paclitaxel or Trastuzumab
 Incidence:
:Heart failure 20% Pacli+Doxo
:Cardiomyopathy 27% Doxo+Trastuzumab

47.  Sequential administration of Paclitaxel followed by
doxorubicin in Breast cancer patients is associated
with cardiomyopathy at total doxorubicin doses
above 340-380 mg/m2
 Whereas the reverse sequence of drug
administration did not yield the same systemic
toxicities

48.  Incidence of cardiomyopathy is related to both
Cumulative dose and schedule of administration
 Cardiac toxicity is corelated with peak plasma
concentration of the parent drug
 Greater cumulative doses of doxorubicin can be
given to patients receiving low dose continuous
infusions than to those receiving higher dose bolus
injections every 3-4 weeks

49. CUMULATIVE DOSES OF DRUGS
DRUG CUMULATIVE DOSE
DOXORUBICIN 400-450 mg/m2
DAUNORUBICIN 800-935 mg/m2
EPIRUBICIN 800-935 mg/m2
IDARUBICIN 223mg/m2
MITOXANTRONE >160mg/m2
5% RISK OF DEVELOPING CADIOMYOPATHY

50. CARDIOTOXICITY REDUCTION STRATEGY
 Liposomal formulations are said to promote tumor
concentrations of the drug while exposing normal
tissue to lower, at best non toxic levels.
 They are associated with higher rates of other toxic
effects such as neutropenia.

51. CO-THERAPY WITH PROTECTIVE AGENTS
DEXRAZOXANE:
 FDA approved to prevent anthracycline induced
cardiotoxicity
 Cumulative dose of Doxorubicin of 300mg/m2
 Benefit from continued treatment
 Metastatic Ca breast
 Dose: 30min before Doxorubicin at a ratio of Dex: Dox
of 10:1

52. MECHANISM OF ACTION
Chelates Iron and copper
Interfering with redox reaction
Decrease generation of free radicals and damage to
myocardial lipids

53. DIFFENCE IN MECHANISM
PACLITAXEL:
 Taxane alkaloid byproduct can affect the cardiac
conduction and automaticity
TRASTUZUMAB:
 Cardiac Her2 is essential for normal embryonic and
adult cardiac development and function
 Blocking of the receptors: Dilated cardiomyopathy

54. NEWER PREVENTION STRATEGIES
Include the use of
 Angiotensin converting enzyme inhibitors
 Angiotension II receptor blockers
 Carvedilol- Has potent anti-oxidant and anti-
apoptotic properties
Ultimate Modality: Cardiac Transplantation

55. MYELOSUPPRESION AND MUCOSITIS
 Important dose limiting toxicity
 Leucopenia more common
 Myelosuppression begins in 7 days following
administration
 Nadir occurs by Day 8-10 followed by recovery by
Day21
 Thrombocytopenia and anemia less severe

56.  Daunorubicin: BM suppression>Mucositis
 Doxorubicin: BM suppression = Mucositis
 With weekly dosing or continuous infusion,
mucositis frequently becomes the dose limiting
toxicity

57. EXTRAVASATION INJURY
 Specific to anthracyclines
 Extravasation leads to severe local injury that can
contribute to progress over weeks to months
 Drug binds locally to tissues
 Local wound care to prevent infection is most important
 T/T: Ice, Steroids, Vit E, Dimethly sulphoxide and
Bicarbonate
 C/I for using Ice packs: Vinca alkaloids and Etoposide

59. INITIAL MEASURES FOR EXTRAVASATION
Stop infusion immediately
Do not flush line and avoid applying pressure to extravasated
site
For peripheral lines: Elevate extremity
Do not remove catheter/needle immediately
Leave in place to attempt aspiration fluid or administration of
antidote
If antidote will not be administered, peripheral catheter/needle
can be removed after attempted administration

60. For Central Venous access Device:
 Antimicrobial therapy
 Pain Control
 Supplemental oxygen
Recently:
 Dexrazoxane + s/c Granulocyte macrophage
colony stimulating factor
 To promote wound healing

61. DOXORUBICIN VS LIPOSOMAL DOXORUBICIN
 Doxorubicin- Strong vesicant
 Besides : Less cardiotoxic; Less nauseous; Less
emetogenic, mild myelosuppressive
UNIQUE TO LIPOSOMAL FORM
 Infusion reaction with flushing, dyspnoea, facial swelling,
headache, back pain, tightness in chest and throat and
hypotension (Even more when given through central
lines)
 Hand foot Syndrome

62. OTHER ADVERSE DRUG REACTIONS:
 Nausea and vomiting
 Hyperpigmentation of nails and urticaria
 Alopecia
 Red orange colour of urine : Lasts 1-2 days after drug
administration
 Erythema at injection site – Flare reaction
 RADIATION RECALL: Increased inflammation in
previously irradiated areas can lead to pericarditis,
pleuritis and skin rashes

63. PATHOPHYSIOLOGY OF RADIATION RECALL
 Stem cells of irradiated area have increased sensitivity
and display a remembered reaction to subsequent
chemotherapy
 Idiosyncratic drug Hypersenstivity reactions that may be
analogous to fixed drug eruptions
 Continued low level secretion of inflammation mediating
cytokines induced by RT. Presence of precipitating
chemotherapy agent may then upregulate these
cytokines
 Keratinocyte necrosis, related to cumulative direct DNA
damage and oxidative stress

64. DELAYED EFFECTS OF ANTHRACYCLINES
Risk of Secondary Malignancy:
 Multiply the risk of developing acute myelogenous
leukemia (Unresponsive to treatment and carries a
poor prognosis).
 Overall absolute risk remains low
(Estimated as <2% at ten years after treatment).

65. TAKE HOME MESSAGE
 Anthracyclines are Topoisomerase II inhibitors
 Widely used in majority of combination chemotherapy regimens
 History of cardiac co-morbidities is very important
 Avoid combining with Trastuzumab
(Approved for Metastatic Gastric cancer)
 Avoid combining with Radiation
 Specific side effects- Cardiotoxicity, extravasation, Radiation recall
phenomenon
 Always counsel patients for red colour of urine
 Never substitute Doxorubicin with Liposomal Doxorubicin