ANTI-CANCER DRUGS

(CYTOTOXIC CHEMOTHERAPY &SALVAGE)

Classification and alkylating agents

Common toxicities of alkylating agents:

1. Myelosuppression (dose-limiting)
• Anemia
• Neutropenia
• Thrombocytopenia
• Pancytopenia
2. Nausea and Vomiting
3. Alopecia
4. Sterility – Gonadal damage
5. Mucositis – oral ulcers
6. Intestinal denudation – Diarrhea
7. Neurotoxicity
• Altered mental status
• Coma
• Seizures
• Ataxia
8. Pulmonary fibrosis
9. Veno-occlusive disease of liver (VOD)
10. Secondary malignancies (mostly AML)

Antimetabolites

Interaction between 6-MP / Azathioprine and XO inhibitors:

6-MP and Azathioprine

↓ Xanthine oxidase
Inactive metabolites
• Hence, XO inhibitors inhibit the metabolism of 6-MP and Azathioprine, increasing their
plasma levels and risk of toxicities.
• Therefore, the doses of 6-MP and azathioprine need to be reduced.

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Drugs for hairy cell leukemia:

• Cladribine (DOC)
• Interferon – α
• Pentostatin
• Vemurafenib (due to presence of V600E BRAF mutations)

Other cytotoxic agents

Metabolism of irinotecan:

Irinotecan
↓ Carboxylesterases in liver
Active metabolite (SN-38)
↓ UGT1A1
Inactivate SN-38 glucuronide

• Polymorphisms in UGT1A1 such as in Gilbert’s syndrome can lead to accumulation of

the drug and drug toxicity.
• Hence, irinotecan should be avoided in patients with UGT1A1 polymorphisms.

Flagellate dermatitis:

• Adverse effect of – Bleomycin

• Bands of pruritic erythema
• Involving arms, back, scalp and hands
• Treatment: Topical steroids

Salvage therapy

Treatment of chemotherapy-induced nausea and vomiting:

Early (< 24 h): Ondansetron

Late (> 24 h): Aprepitant

Treatment of chemotherapy-induced myelosuppression:

CHEMOTHERAPY-INDUCED PREFERRED TREATMENT

Anemia Erythropoietin
Neutropenia Filgrastim
Thrombocytopenia Oprelvekin (rIL11)

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ANTI-CANCER AGENTS - (TARGETED THERAPY)

Hormonal agents

Tamoxifen:

SERM – Selective Estrogen Receptor Modulator

Agonist:
• Bone
• Uterus
• (+ CVS)
Antagonist:
• Breast

Fulvestrant:

• SERD (Selective Estrogen Receptor Down-regulator)

• Antagonist at all estrogen receptors
• Also known as ‘Pure anti-estrogen’
• Approved for – metastatic ER +ve breast cancer
• Dose: 250 mg IM once monthly in the buttocks
• Long T½: ~ 40 days

Aromatase inhibitors:

Examples:
• Letrozole
• Anastrozole
• Exemestane (irreversible)

Tyrosine kinase and protein synthesis inhibitors

Erlotinib:

• Competitive inhibitor of ATP binding to EGFR1 (ErbB1)

• Oral bioavailability significantly increased by food – NOT given with food to avoid
toxicity
• Approved for locally advanced / metastatic non-small cell lung CA

Gefitinib different from erlotinib:

• Oral bioavailability not affected by food – can be given irrespective of meals

• Approved for – Refractory non-small cell lung CA

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Hand-foot syndrome (HFS) v/s Hand-foot-skin reaction (HFSR):

HAND-FOOT
HAND-FOOT SKIN REACTION (HSFR)
SYNDROME (HFS)
Lesions Diffuse Sharply demarcated
Areas involved Palms and soles Heels, metatarsal heads, other areas
of friction
Characteristics Erythema and edema Erythmatous, edematous, tender
blisters that may evolve into painful
calluses
Pain Painful Painful
Associated Capecitabine Drugs inhibiting multiple tyrosine
with 5-FU kinases

Monoclonal antibodies – 1 (Production, anti-TNF-alpha agents and Bevacizumab)

Anti-TNF-α antibodies:

Indications:
• RA
• AS
• Plaque psoriasis (including psoriatic arthritis)
• Crohn’s disease
Contraindications:
1. Active infection / High risk of infection (including TB)
2. Malignancy / Pre-malignancy
3. Immune suppressed state (including HIV)
4. Hepatitis B
5. SLE
6. Multiple sclerosis
7. CHF
8. Pregnancy
9. Lactation

Adverse effects of Bevacizumab:

• Potential for vessel injury and bleeding → Pulmonary haemorrhages

• Arterial thromboembolic events – stroke or MI
• Hypertension. If poorly controlled → reversible posterior leukoencephalopathy or CHF
• GI perforation

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 • Asymptomatic proteinuria (more common in CA ovary and primary colon CA)

Monoclonal antibodies – 2 (Remaining antibodies)

Reactivation of JC and BK viruses associated mainly with – Rituximab

Dose of basiliximab: 2 doses of 20 mg each

1st dose: within 2 hours prior to transplant
2nd dose: 4 days after transplant

Examples of some of the monoclonal antibodies:

Drug (M.ab) Target Indication

Catumaxomab CD3 and EpCAM Malignant ascites
Ramucirumab VEGFR 2 Gastric CA
Lung CA
Panitumumab EGFR Colorectal CA
Trastuzumab HER2/neu (EGFR2) Breast CA

Immunosuppressants

Adverse effects of calcineurin inhibitors:

Cyclo > Tacro Tacro > Cyclo

• Hypertension • Nephrotoxicity
• Hirsutism • Neurotoxicity
• Hyperplasia of gums • Hepatotoxicity
• Diabetes mellitus
• Diarrhea
• Alopecia

Drugs for rheumatoid arthritis:

(A): CONVENTIONAL DMARDs

• Methotrexate
• Sulfasalazine
• Hydroxychloroquine
• Leflunomide

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(B): BIOLOGIC DMARDs:
TARGET DRUGS
TNF-α • Infliximab
• Adalimumab
• Etanercept
• Golimumab
• Certolizumab
CD80/86 Abatacept
IL-6 Tocilizumab
JAK Tofacitinib

(C): NON-DMARDs (only for symptomatic relief)

• NSAIDs
• Steroids

Immunostimulants

Adverse effects of thalidomide:

1. Sedation
2. Constipation
3. Peripheral neuropathy (most serious)
4. Fatigue
5. Deep vein thrombosis
6. Hypothyroidism
7. Teratogenicity
• Phocomelia
• Mobius syndrome
Anti-cancer drugs causing peripheral neuropathy:
1. Vinca alkaloids
2. Taxanes
3. Platinum analogues
4. Thalidomide
5. Bortezomib
Indications of Interferon-α:
• Hairy cell leukaemia
• Follicular lymphomas
• Malignant melanoma

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• AIDS-related Kaposi’s sarcoma
• Mycosis fungoides
• Condyloma acuminata
• Chronic hepatitis B
• Chronic hepatitis C (+ Ribavirin)

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