1. Antineoplastic Prescribing I
Brian Boulmay, MD
LSU- Section of HemOnc

2. It’s the dose that makes a poison.
Paracelcus
AD 1520

3. Objectives Understand the basis for chemotherapy.
Be able to identify appropriate dosage ranges.
Be able to identify major toxicities.
Learn the skill of prescribing chemotherapy.

4. To be a monk, you have to cook a lot of rice.
-David Lee Roth

5. Overview Cell Cycle Kinetics
Pharmacologic Classification of Antineoplastic Agents
Review of Agents
Review of Combination Therapy
Therapy

6. The Cell Cycle Mitosis Premitotic M RNA Synthesis Protein Synthesis G2
DNA Synthesis

7. Therapy Basics Phase Specific drugs Phase Non-Specific drugs
work only on a specific phase of cell growth
most effective in rapidly growing cells
Phase Non-Specific drugs
work on more than one phase of cell growth

8. Chemotherapy terms
Induction therapy- used as primary treatment (leukemia).
Consolidation- drug therapy used as follow up after remission from induction (leukemia).
Adjuvant- drug therapy after surgery or XRT.
Neo-adjuvant- drug therapy before surgery or XRT which is not adequate for cure
Salvage- drug therapy when primary drug treatment fails
Definitive- Chemotherapy used for cure

9. Chemotherapy terms
Regional -drug therapy localized to a specific area (e.g. limb perfusion, intrathecal, intraperitoneal)
Maintenance -drug therapy used to maintain stable disease or remission.
High Dose -doses above the standard range used primarily in combo with bone marrow rescue. Assumption that dose- intensity is effective.
Palliation -drug therapy given to reduce symptoms without an intent to cure disease.

10. Response criteria
Complete Response -Complete disappearance of signs and symptoms for at least 1 month.
Partial Response ->50% reduction of tumor mass of all measured lesions and no new lesions.
Stable Disease -No significant change in tumor mass neither increasing or decreasing by 25%.
Progressive Disease- More than 25% increase in tumor mass

13. Chemotherapy- Acute lymphoblastic leukemia
Single agents- late 1940’s
Antimetobolites or nitrogen mustards= Short remissions
NCI/ Roswell Park/ Childrens’ Buffalo- 1950’s
Methotrexate + 6-mercaptopurine= Longer remissions

14. Therapy Concepts Goldie-Coldman Hypothesis–
A fraction of tumor cells will develop resistance after treatment.
This clone will continue to grow even in responders.
Alternating combinations of chemotherapy agents= prevent resistant clones

15. Combination Chemotherapy- Acute lymphoblastic leukemia
Multiple agents:
Vincristine + amethopterin + 6MP + prednisone= Cure
21st century:
Children: Cure is the rule
Adults: 40% cure rate

16. Combination chemotherapy
DeVita- MOPP for stage IV Hodgkin lymphoma= Cure
Bonnadonna- CMF chemotherapy after breast cancer surgery= More cures than with surgery

17. Combination chemotherapy- Advantages
Maximum cell kill
Broad coverage of resistant cell lines
Prevent development of resistance
Method
–Use only effective drugs
–Use optimal scheduling and dose
Limit overlapping toxicities

18. Combination chemotherapy- Disadvantages
Multiple toxicities.
Reduction or holding of doses due to toxicity will limit effectiveness.
Complicated to administer.
Expensive.

19. Combination Therapy Toxicity
Combination Therapy Toxicity- FAC
5-Fluorouracil, Adriamycin, Cytoxan (cyclophosphamide)
Toxicity
Responsible Drug
Alopecia
C,A
Cardiotoxicity A
Cystitis C
Myelosuppression
C, A, F
Mucositis
A, F

20. Factors Affecting Tumor Response
Tumor Burden
Tumor Site
Tumor Heterogeneity
Drug Resistance
Dose Intensity
Patient Specific Factors
Apoptosis

21. Cell Cycle Specific Drugs
S Phase Specific Drugs
Antimetabolites:
Folate antagonists ???
Purine antagonists ???
Pyrimidine antagonists ???

22. Cell Cycle Specific Drugs
S Phase Specific Drugs
Antimetabolites:
Folate antagonists (methotrexate)
Purine antagonists (cladribine, fludarabine)
Pyrimidine antagonists (cytarabine, fluorouracil)

23. Cell Cycle Specific Drugs
Mitosis Phase Specific Drugs
Vinca Alkaloids (vincristine, vinblastine)
Taxanes (paclitaxel, docetaxel)
G2 Phase Specific Agents–
Topoisomerase I Inhibitors (irinotecan)
Topoisomerase II Inhibitors (etoposide)
G1 Phase Specific Agents
Enzymes (asparaginase)

24. Cell Cycle Non-Specific Drugs
Alkylating Agents
Anthracyclines
Antibiotics
Tyrosine Kinase Inhibitors

25. Alkylating Agents Cell Cycle Non-Specific
Major Toxicity: Myelosuppression, alopecia
Examples:
Busulfan (Myleran)
Dacarbazine (DTIC)
Cyclophosphamide, Ifosfamide
Melphalan

26. Alkylating Agents
Mustards: Ifosfamide, cyclophosphamide, nitrogen mustard
Alkylation: Addition of an alkyl group to guanine
Prevents coiling or uncoiling of DNA by crosslinking guanine H C H H
Methyl group

27. Alkylating Agents Dacarbazine Indications Toxicities Hodgkin Lymphoma
Myelosuppression
Nausea, nausea
Irritant
Dacarbazine

28. Alkylating Agents Indications Toxicities ALL Cystitis Breast
Myelosuppression
NHL
Irritant
Nausea, nausea
cyclophosphamide (Cytoxan)

29. Cyclophosphamide Cyclophosphamide Liver Aldophosphamide
Phosphoramide mustard
(active metabolite)
Acrolein
(cause of hemorrhagic cystitis)

30. Ifosfamide Indications Common Toxicities Sarcoma Myelosuppression NHL
Nausea, nausea
Testicular
Cystitis
Ifos Brain

31. (cause of neuro compromise)
Ifosfamide
Ifosfamide
chloroacetaldehyde
(cause of neuro compromise)
aldoifosfamide
acrolein
isophosphoramide mustard

32. Alkylating Agents Other alkylators: Procarbazine Chlorambucil
Mechlorethamine

33. Nitrosureas Mechanism: Bind to DNA causing breaks/ alkylators
Cell Cycle Non-Specific
Examples
Carmustine (BCNU)
Lomustine (CCNU)

34. Nitrosureas Indications Toxicity CNS Tumors
delayed neutropenia (3-5 weeks after dose)
nausea
irritant
Administered IV
BCNU (carmustine)

35. Nitrosureas Indications Toxicity CNS Tumors
delayed neutropenia (3-5 weeks after dose)
nausea
irritant
Administered PO
CCNU (lomustine)

36. Platinum Analogues Mechanism: Form Crosslinks in DNA, RNA
Cell Cycle Non-Specific
Major Toxicity: Renal and nausea/vomiting
Examples:
Cisplatin
Carboplatin
Oxaliplatin

37. Cisplatin cis-diamminedichloroplatinum (CDDP)
Through a process of ‘aquation,’ platinum is able to bind DNA bases (guanine)
A second binding to another guanine results in “cross-linking’ of DNA.

38. Cisplatin
25% of a dose is excreted in the urine within 1 hour of a dose
75% rapidly distributes in skin, muscle and liver.
cisplatin can be measured in urine months after a single dose
Extensive protein and RBC binding
Important for dosing methodology (versus carboplatin)

39. Cisplatin Indications Toxicity Lung Renal dysfunction Testicular
Hypomagnesemia
Head and neck
Nausea
Bladder
Neuro-ototoxcity
Ovarian
Peripheral neuropathy (prolonged use)

40. Carboplatin cis-diammine(1,1-cyclobutanedicarboxylato)platinum
Lower reactivity, less protein binding than cisplatin
More stable in D5W rather than NS

41. Carboplatin
Renal function and other physiologic variables can affect excretion:
Carboplatin typically dosed by the area under the curve (AUC) mg/ml x min
mg/m2 a less reliable method: hematologic toxicity higher
Calvert Equation:
dose=Target AUC x [GFR+25]

42. Carboplatin
Percentage reduction in platelet count linearly correllates with the AUC.
AUC6 targets plt count nadir 100K
Advantages of AUC:
Avoids subtherapeutic dosing for patients with high GFR
Avoids overdosing those with renal impairment
Calvert JCO 1989

43. Platinum Analogues Oxaliplatin Indications Common Toxicities
Colon cancer
90% neuropathy
myelosuppression
Oxaliplatin

44. Anthracyclines
Mechanism: Intercalate DNA base pairs; generates iron mediated free O radicals
Cell Cycle Non-Specific
Major Toxicity: Cardiac, Vesicant, Alopecia
Examples:
Doxorubicin (Adriamycin) ----Red
Daunorubicin Red
Idarubicin (Idamycin) Red
Epirubicin (Ellence) Red
Mitoxantrone (Novantrone) Blue

45. Anthracyclines Toxicity:
Cardiac toxicity possibly related to inhibition of topoisomerase II in cardiomyocytes.
Typically dose related

46. Anthracyclines Drug Lifetime Dose Doxorubicin 500-550mg/m2
Daunorubicin
mg/m2
Doxorubicin+cyclophophosphamide
450mg/m2
Epirubicin
mg/m2
Epirubicin+cyclophosphamide
750mg/m2
Idarubicin
~120mg/m2
Mitoxantrone
160mg/m2
Keefe Semin Oncol 2001

47. Anthracyclines Conversion Table: Drug Conversion Factor
Doxorubicin- 5% HF at 450mg/m2 1
Daunorubicin- 5% HF at 900mg/m2
0.5
Epirubicin- 5% HF at 935mg/m2
Idarubicin- 5% HF at 225mg/m2 2
Mitoxantrone- 5% HF at 200mg/m2
2.2

48. Anthracyclines Drug considerations: Vesicant Hepatically cleared:
T bili >1.5 or AST >2x ULN: dose adjustment necessary
Contraindicated in heart failure

49. Anthracyclines Adriamycin “Red Drug” Idarubicin Indications Toxicity
Breast
Myelosuppression
Bladder
Nausea
NHL
Mucositis
Hodgkin
Vesicant
Sarcoma
Indications
Common Toxicities
AML
Myelosuppression
ALL
Nausea
Cardiac dysfunction
Adriamycin
“Red Drug”
Idarubicin

50. Antibiotics
Mechanism: DNA breakage- exact mechnism of action still unclear.
Cell Cycle Non-Specific
Major Toxicity: Pulmonary and Renal
Examples:
Mitomycin
Bleomycin

51. Antibiotics Mitomycin Bleomycin Indication Common Toxicity Anal
Myelosuppression
HUS
Vesicant
Indications
Toxicity
Testicular
Pulmonary fibrosis*
NHL
Anaphylaxis
Fever
Mitomycin
Bleomycin

52. A few words on pulmonary toxicity
Bleomycin:
Avoid high 02 concentrations for several weeks post chemo
Incidence is 1-3% when doses >400 units
Symptoms include dyspnea and dry cough
Incidence of pulmonary toxicity with bleomycin increased from 9% to 26% with use of growth factors and ABVD (Martin JCO 2005)
At what threshold of FEV1 or DLCO do you hold bleomycin?

53. A few words on pulmonary toxicity
Bleomycin:
Avoid high 02 concentrations for several weeks post chemo
Incidence is 1-3% when doses >400 units
Symptoms include dyspnea and dry cough
Incidence of pulmonary toxicity with bleomycin increased from 9% to 26% with use of growth factors and ABVD (Martin JCO 2005)
At what threshold of FEV1 or DLCO do you hold bleomycin?
Unknown:
‘Bleomycin was discontinued if the patient manifested clinical or radiographic evidence of pulmonary fibrosis (rales or inspiratory lag) or significant deterioration of pulmonary diffusion capacity. ‘ (Nichols JCO 1998)

54. Antimetabolites: Folate Antagonists
Mechanism: Inhibits dihydrofolate reductase
Inhibits tetrahydrofolic acid production
Cell Cycle Specific: S Phase
Major Toxicity: Myelosuppression & GI
Example
Methotrexate
Pemetrexed

55. Antimetabolites: Folate Antagonists
Indications
Toxicities
ALL
Renal
Sarcoma
Mucositis
NHL
Head and Neck Cancer
Indications
Toxicities
Non-small cell lung cancer
Fatigue
Skin Rash
Conjunctival Irritation
Methotrexate (MTX)
Pemetrexed

56. Pemetrexed/ MTX- Special Considerations
MTX- Effusions
Pemetrexed is safe with effusions.
Pemetrexed-
Coadministration:
with B12 q 9 weeks
Daily 1mg folic acid
Dickgreber Clin Cancer Researcher 2010

57. High Dose Methotrexate
Rescue with leucovorin after completion of 24 hour infusion.
Dosing nomogram based on daily MTX levels:
Mechanism of action of leucovorin?

58. High Dose Methotrexate
Rescue with leucovorin after completion of 24 hour infusion.
Dosing nomogram based on daily MTX levels:
Mechanism of action of leucovorin?
Donates methyl groups.
Allows for purine/pyrimadine synthesis.

59. Antimetabolites: Pyrimadine Anatagonists
Mechanism: Inhibits thymidylate synthetase
Cell Cycle Specific: S Phase
Major Toxicity: Myelosuppression
Examples
Cytarabine
Fluorouracil
Capecitabine
Gemcitabine

60. Antimetabolites: Pyrimadine Anatagonists
Indications
Common Toxicities
Colon
Myelosuppression
Breast
Mucositis (CIVI)
Head and Neck
Diarrhea
Gastric
Hand-foot syndrome
Indications
Toxicity
AML
Myelosuppression
ALL
Cerebellar Toxicity
NHL
Ocular (conjunctival)
Cytarabine
5-Fluorouracil

61. Antimetabolites: Pyrimadine Anatagonists
Indications
Toxicity
Breast
Diarrhea
Colon
Hand/Foot Syndrome
Capecitabine (Xeloda)

62. Antimetabolites: Purine Antagonists
Mechanism: Inhibits ribonucleotide reducatase
Cell Cycle Specific: S Phase
Major Toxicity: Myelosuppression
Examples
Cladribine
Fludarabine
Mercaptopurine

63. Antimetabolites: Purine Antagonists
Indications
Toxicity
Hairy Cell Leukemia
Myelosuppression
Fever
Indications
Toxicity
NHL
Myelosuppression
CLL
AML
Fludarabine
Cladrabine

64. Fludarabine- Special Considerations
Leukopenia
Deep and sustained
Do not use G-CSF support to keep patients ‘on time’
Gets worse before it gets better.
‘AIDS-level’ drops in CD4 counts:
Prophylaxis with acyclovir and Bactrim during and for at least 6 months after therapy.

65. Vinca Alkaloids Mechanism: Inhibits spindle formation
Cell Cycle Specific: M Phase
Major Toxicity: Neuropathy, alopecia, vesicants
Examples
Vincristine
Vinblastine
Vinorelbine

66. Vinca Alkaloids Vincristine* Vinblastine Indications Toxicity
Hodgkin Lymphoma
Myelosuppression
Neuropathy
Indications
Toxicity
ALL
Neuropathy
NHL
Constipation
CLL
Ileus
Breast
Vincristine*
*Never give Intrathecal
Vinblastine

67. Vesicants vs. Irritants
(blistering agents)
Irritants
Anthracyclines
(except mitoxantrone)
Cisplatin
Vinca alkaloids
Carboplatin
Mechlorethamine
Taxanes
Mitoxantrone
Etoposide (VP-16)

69. Treatment of extravasation
Stop infusion
Do not remove catheter.
Aspirate as much as possible
Instill antidote into effected area:
Sodium thiosulfate for mechlorethamine, platinums
Hyaluronidase for units for vincas
Apply cold compresses 45 minutes on/ 15 minutes off for 24 hours
Apply warm compresses for vincas, etoposide, and taxanes

70. Topoisomerase inhibitors: Topo 1
Mechanism: Inhibit Topoisomerase I
Cell Cycle Specific: G2 Phase
Major Toxicity:Diarrhea,Myelosuppression
Examples
Irinotecan
Topotecan

71. Topo1 Inhibitors Topotecan Irinotecan (CPT-11) Indications Toxicity
Colon
Diarrhea
SCLC
Myelosuppression
Gastric
Flushing
Alopecia
Indications
Toxicity
Lung
Myelosuppression
Ovarian
Diarrhea
Topotecan
Irinotecan (CPT-11)

72. Irinotecan- Special Considerations
Diarrhea-
Acute: Inhibition of acetylcholinesterase
Atropine prophylactically/ secondary treatment
Chronic:
SN-38 secreted in bile.
Loperamide, Lomotil

73. Topo II: Epipodophyllotoxins
Mechanism: Inhibit Topoisomerase II
Cell Cycle Specific: G2 Phase
Major Toxicity: Myelosuppression, Mucositis
Example:
Etoposide

74. Topo II: Inhibitors Etoposide (VP-16)* Indication Toxicity Lung
Myelosuppression
NHL
Mucositis
Testicular
Etoposide (VP-16)*

75. Topo II: Inhibitors Etoposide (VP-16)* Indication Toxicity Lung
Myelosuppression
NHL
Mucositis
Testicular
Etoposide (VP-16)*
*Peculiar Leukemia Risk: 1-2% AML risk at 2 years
MLL gene, 11q23

76. Taxanes Mechanism: Stabilizes Microtubules
Cell Cycle Specific: M Phase
Major Toxicity: Myelosuppression, Neuropathy, *Allergic Reactions, Alopecia
Examples:
Paclitaxel*
Docetaxel

77. Taxanes Paclitaxel Docetaxel Indications Toxicity Breast Neuropathy
Lung
Alopecia
Ovarian
Myelosuppression
Head and Neck
Indications
Toxicities
Breast
Myelosuppression
Lung
Hypersensitivity
Head and Neck
Angioedema
Alopecia
Paclitaxel
Docetaxel

78. Antineoplastics II- Next time