CHEMOTHERAPY AGENTS;ONCOLOGY

1. ALKYLATING
AGENTS
DR. AADITYA PRAKASH
DNB RT , RESIDENT
BMCHRC , JAIPUR

4. CLASSIFICATION

5. MECHANISM OF ACTION
• Alkylating agents target DNA and are cytotoxic, mutagenic, and
carcinogenic.
• All agents produce alkylation through the formation of intermediates.
• Alkylating agents impair cell function by transferring alkyl groups to
amino, carboxyl, sulfhydryl, or phosphate groups of biologically
important molecules.

6. MECHANISM OF ACTION
• Most important, nucleic acids (DNA and RNA) and proteins are
alkylated.
• The number 7 (N-7) position of guanine in DNA and RNA is the most
actively alkylated site; the O-6 group of guanine is alkylated by
nitrosoureas.
• Alkylation of guanine results in abnormal nucleotide sequences,
miscoding of messenger RNA, cross-linked DNA strands that cannot
replicate, breakage of DNA strands, and other damage to the
transcription and translation of genetic material.

7. MECHANISM OF ACTION
• Cross-linking of DNA appears to be of major importance to the
cytotoxic action of alkylating agents, and replicating cells are most
susceptible to these drugs.
• Alkylating agents are cell cycle-non specific.
• The drugs kill a fixed percentage of cells at a given dose.

8.  A bis(chloroethyl)amine forms an ethyleneimonium ion that reacts with a base such
as N7 of guanine in DNA, producing an alkylated purine.
 Alkylation of a second guanine residue, through the illustrated mechanism, results in
cross-linking of DNA strands.

9. RESISTANCE
• Increased capability to repair DNA lesions
• Decreased transport of the alkylating drug into the cell
• Increased expression or activity of glutathione and glutathione-associated
proteins, which are needed to conjugate the alkylating agent, or increased
glutathione S-transferase activity, which catalyzes the conjugation
• Increased scavenging of drug species by nonessential cellular nucleophiles
• Increased enzymatic detoxification of drug species
• Altered expression of genes coding for cellular commitment to apoptosis

10. ADVERSE EFFECTS
• NAUSEA AND VOMITING
• BONE MARROW TOXICITY
• HEMORRHAGIC CYSTITIS :–
• Unique to the oxazaphosphorines (cyclophosphamide and ifosfamide)
• Caused by the excretion of toxic metabolites (particularly acrolein)
• Incidence and severity can be lessened by:-
1. Adequate hydration and continuous irrigation of the bladder with a
solution containing 2-mercaptoethane sulfonate (MESNA) and frequent
bladder emptying.
2. MESNA Is given in divided doses every 4 hours in dosages of 60% of
those of the alkylating agent.

11. ADVERSE EFFECTS
• INTERSTITIAL PNEUMONITIS AND PULMONARY FIBROSIS
• GONADAL TOXICITY :-
1. Depletion of testicular germ (but not sertoli) cells
2. Patients in remission and off alkylating agents for 2 to 7 years show complete
spermatogenesis, indicating that testicular damage is reversible.
• TERATOGENESIS :-
• Administration of alkylating agents during the first trimester of pregnancy
presents a definitive risk of a malformed fetus
• But the administration of such drugs during the second and third trimesters does
not increase the risk of fetal malformation above normal.
• CARCINOGENESIS : e.g fulminant acute myeloid leukemia
• ALOPECIA
• ALLERGIC REACTIONS
• IMMUNOSUPPRESSION

12. IMPORTANT CLINICALLY USEFUL
ALKYLATING AGENTS
CISPLATIN
TRADE NAME :- CIS-DIAMMINEDICHLOROPLATINUM, CDDP,
PLATINOL

13. ABSORPTION:
• Not absorbed orally.
• Systemic absorption is rapid and complete after intraperitoneal (IP)
administration
INDICATIONS:
1. TESTICULAR CANCER.
2. OVARIAN CANCER.
3. BLADDER CANCER.
4. HEAD AND NECK CANCER.
5. ESOPHAGEAL CANCER.
6. SMALL CELL AND NON–SMALL CELL LUNG CANCER.
7. NON-HODGKIN’S LYMPHOMA.
8. TROPHOBLASTIC NEOPLASMS.

14. DOSAGE RANGE:
• OVARIAN CANCER—
1. 75 mg/m2 IV on day 1 every 21 days as part of the cisplatin/paclitaxel regimen
2. 100 mg/m2 on day 1 every 21 days as part of the cisplatin/cyclophosphamide
regimen.
• TESTICULAR CANCER— 20 mg/m2 IV on days 1–5 every 21 days as part of the
PEB regimen
• HEAD AND NECK CANCER— 100 mg/m2/day IV on day 1 every 21 days
• NON–SMALL CELL LUNG CANCER— 60–100 mg/m2 IV on day 1 every 21
days as part of the cisplatin/etoposide or cisplatin/gemcitabine regimens
• METASTATIC BREAST CANCER- 20 mg/m2 (IV, days 1–5 every 3 wks)
• CERVICAL CANCER- 70 mg/m2 (IV, dosing cycled every 4 wks)
• ESOPHAGEAL CANCER- 75 mg/m2 on day 1 of wks 1, 5, 8, and 11 (IV)

15. SPECIAL CONSIDERATIONS:
• Contraindicated in patients with known hypersensitivity to cisplatin or other
platinum analogs
• Creatinine clearance should be obtained at baseline and before each cycle of
therapy
• Patients must be hydrated before, during, and post-drug administration
• Baseline audiology exam and periodic evaluation during therapy are
recommended to monitor the effects of drug on hearing.
• Contraindicated in patients with pre-existing hearing deficit
• Prophylaxis against delayed emesis (>24 hours after the drug administration)
is also recommended.
• A combination of a 5-HT3 antagonist (e.g., Ondansetron or Granisetron) and
dexamethasone is standard therapy for prevention of nausea and vomiting.
• Avoid aluminum needles when administering the drug because precipitate
may form, resulting in decreased potency

16. CARBOPLATIN
TRADE NAME:- PARAPLATIN, CBDCA

17. ABSORPTION:
Not absorbed by the oral route. Only I/V
INDICATIONS:
1. OVARIAN CANCER.
2. GERM CELL TUMORS.
3. HEAD AND NECK CANCER.
4. SMALL CELL AND NON–SMALL CELL LUNG CANCER.
5. BLADDER CANCER.
6. RELAPSED AND REFRACTORY ACUTE LEUKEMIA.
7. ENDOMETRIAL CANCER.

18. DOSAGE RANGE:
• Usually calculated to a target area under the curve (AUC) based on the
glomerular filtration rate (GFR)
• Calvert formula is used to calculate dose—total dose (mg) 5 (target
AUC) 3 (GFR 1 25). Note: dose is in mg NOT mg/m2.
• Target AUC is usually between 5 and 7 mg/ml/min for previously
untreated patients.
• Previously treated patients, lower AUCS (between 4 and 6 mg/ml/min)
are recommended.

19. SPECIAL CONSIDERATIONS:
• Contraindicated in patients with known hypersensitivity to cisplatin or
other platinum analogs
• Creatinine clearance should be obtained at baseline and before each
cycle of therapy
• Pregnancy category D. Breastfeeding should be avoided
• Avoid aluminum needles when administering the drug because
precipitate may form, resulting in decreased potency
• Myelosuppression is significant and dose-limiting. Thrombocytopenia is
most commonly observed, with nadir by day 21.

20. OXALIPLATIN
• TRADE NAME:- ELOXATIN, DIAMINOCYCLOHEXANE PLATINUM

21. ABSORPTION
• Not orally bioavailable.
INDICATIONS
• METASTATIC COLORECTAL CANCER— FDA -Approved in
combination with infusional 5-FU/LV in patients with advanced, metastatic
disease.
• EARLY-STAGE COLON CANCER—FDA -Approved as adjuvant therapy
in combination with infusional 5-FU/LV in patients with stage III and with
high-risk stage II colon cancer.
• METASTATIC PANCREATIC CANCER.
• METASTATIC GASTRIC CANCER and GASTROESOPHAGEAL
CANCER.

22. DOSAGE RANGE:
• Recommended dose is 85 mg/m2 IV over 2 hours, on an every 2-week
&/OR 100–130 mg/m2 IV on an every 3-week SCHEDULE.
SPECIAL CONSIDERATIONS
• Use with caution in patients with abnormal renal function
• Careful neurologic evaluation should be performed before starting
therapy.
• Caution patients to avoid exposure to cold following drug
administration:- worsen acute neurotoxicity.

23. SPECIAL CONSIDERATIONS
• Calcium/magnesium infusions (1 gm calcium gluconate/1 gm magnesium
sulfate) prior to and at the completion of the oxaliplatin infusion can be
used to reduce the incidence of acute neurotoxicity.
• Oxaliplatin should not be administered with basic solutions (e.g., Solutions
containing 5-FU), as it may be partially degraded.
• Pregnancy category D. Breastfeeding should be avoided.
• Unlike cisplatin, oxaliplatin does not accumulate to any significant level
after multiple courses of treatment. This may explain why neurotoxicity
associated with oxaliplatin is reversible.

25. CYCLOPHOSPHAMIDE
• TRADE NAME:- CYTOXAN, CTX

26. ABSORPTION
• Well-absorbed by the GI tract with a bioavailability of nearly 90%
INDICATIONS
1. BREAST CANCER.
2. NON-HODGKIN’S LYMPHOMA.
3. CHRONIC LYMPHOCYTIC LEUKEMIA.
4. OVARIAN CANCER.
5. BONE AND SOFT TISSUE SARCOMA.
6. RHABDOMYOSARCOMA.
7. NEUROBLASTOMA
8. WILMS’ TUMOR.

27. DOSAGE RANGE:
• BREAST CANCER—
1. Orally, the usual dose is 100 mg/m2 PO on days 1–14 given every 28
days.
2. IV, the usual dose is 600 mg/m2 given every 21 days as part of the
AC or CMF regimens.
• NON-HODGKIN’S LYMPHOMA—750 mg/m2 on day 1 every 21
days, as part of the CHOP regimen.
• HIGH-DOSE BONE MARROW TRANSPLANTATION— Usual dose
in the setting of bone marrow transplantation is 60 mg/kg IV for 2 days.

28. SPECIAL CONSIDERATIONS:
• Use with caution in patients with abnormal RFT
• Administer oral form of drug during the daytime
• Encourage fluid intake of at least 2–3 L/day to reduce the risk of
hemorrhagic cystitis.
• Encourage patients to empty bladder several times daily (on average,
every 2 hours) to reduce the risk of bladder toxicity.
• Pregnancy category D. Breastfeeding should be avoided.
• Myelosuppression is dose-limiting.

29. CARMUSTINE
• TRADE NAME:- BCNU, BISCHLOROETHYLNITROSOUREA

30. ABSORPTION
• Not absorbed via the oral route.
INDICATIONS
1. BRAIN TUMORS— Glioblastoma Multiforme, Brain Stem Glioma,
Medulloblastoma,astrocytoma, And Ependymoma.
2. HODGKIN’S LYMPHOMA.
3. NON-HODGKIN’S LYMPHOMA.
4. MULTIPLE MYELOMA.
5. GLIOBLASTOMA MULTIFORME— Implantable BCNU -
impregnated wafer (GLIADEL).
6. CUTANEOUS T-CELL LYMPHOMA

31. DOSAGE RANGE:
• Usual dose is 150-200 mg/m2 IV every
6 weeks.
• Implantable BCNU -impregnated
wafers– up to eight wafers (61.6 mg) are
placed into the surgical resection site
after excision of the primary brain
tumor.
• Cutaneous t-cell lymphoma 200–600 mg
(topical solution)

33. SPECIAL CONSIDERATIONS:
• PFTs should be obtained at baseline and monitored periodically during
therapy.
• At cumulative doses greater than 1400 mg/m2 interstitial lung disease
and pulmonary fibrosis develops.
• Administer carmustine slowly over a period of 1–2 hours to avoid
intense pain and/or burning at the site of injection.
• Monitor CBC while on therapy.
• Pregnancy category D. Breastfeeding should be avoided.

34. TEMOZOLOMIDE
• TRADE NAME:- TEMODAR

35. MECHANISM OFACTION
• Methylates guanine residues in DNA and inhibits DNA, RNA, and
protein synthesis synthesis and function
• Does not cross-link DNA strands
MECHANISM OF RESISTANCE
• Increased activity of DNA repair enzymes such as O6-alkylguanine
DNA alkyltransferase.

36. ABSORPTION
• Rapidly and completely absorbed with an oral bioavailability
approaching 100%. Maximum plasma concentrations are reached within
1 hour after administration.
• Food reduces the rate and extent of drug absorption.
INDICATIONS
• For refractory anaplastic astrocytomas at first relapse
• Newly diagnosed glioblastoma multiforme (GBM)
• Metastatic melanoma.

37. DOSAGE RANGE:
• Temozolomide is given at 75 mg/m2 PO daily for 42 days along with
radiotherapy (60 Gy in 30 fractions) for newly diagnosed GBM.
• During the maintenance phase, which is started 4 weeks after completion of
the combined modality therapy, Temozolomide is given on cycle 1 at 150
mg/m2 PO daily for 5 days followed by 23 days without treatment.
RESULTS
• 2 YR OS –– 27% VS 10%
• STUPP R. et al RADIOTHERAPY PLUS CONCOMITANT AND
ADJUVANT TEMOZOLOMIDE FOR GLIOBLASTOMA. N . ENGL J
MED 2005 352(10):987––996.

38. SPECIAL CONSIDERATIONS
• Monitored closely for the development of PCP. Require PCP
prophylaxis.
• Prophylaxis with Trimethoprim/Sulfamethoxazole (Bactrim DS) 1 tablet
PO bid, 3 times per week to reduce the risk of Pneumocystis jiroveci
infection.
• Increased risk for myelosuppression.
• To avoid sun exposure.
• Pregnancy category D. Breastfeeding should be discontinued.

39. OTHER USEFUL ALKYLATING AGENTS

40. OTHER USEFUL ALKYLATING
AGENTS

41. OTHER USEFUL ALKYLATING
AGENTS

42. ANTI-METABOLITES
DR. AADITYA PRAKASH
DNB RT , RESIDENT
BMCHRC , JAIPUR

44. MECHANISM OF ACTION
• Antifolate compounds are tight-binding inhibitors of DHFR
(dihydrofolate reductase), enzyme in folate metabolism.
• Results in inhibition of the synthesis of tetrahydrofolate (THF)-
key one-carbon carrier for enzymatic processes involved in
denovo synthesis of thymidylate, purine nucleotides, and the
amino acids serine and methionine.
• Thereby interferes with the formation of DNA, RNA, and key
cellular proteins.
• Their activity is greatest in the S phase of the cell cycle.(CCS)

45. MECHANISM OF ACTION
• PURINE ANTAGONISTS inhibit enzymes involved in de novo purine
synthesis and purine interconversion reactions.

46. RESISTANCE
• Alteration in antifolate transport.
• Increased expression of the catabolic enzyme γ-glutamyl hydrolase.
• Alterations in the target enzymes DHFR and/or thymidylate synthase
(TS) through increased expression of wild-type protein or
overexpression of a mutant protein.
• Gene amplification.
• Decreased expression of mismatch repair enzymes.(hMLH1, hMSH2)

47. ADVERSE EFFECTS
• Dose-limiting myelosuppression
• Gastro-intestinal (GI) toxicity
• Acute elevations in hepatic enzyme levels and hyperbilirubinemia (with
high doses)
• Mucositis, skin rash (hand-foot syndrome)

48. METHOTREXATE
• TRADE NAME:- MTX, AMETHOPTERIN

49. ABSORPTION
• Oral bioavailability is saturable and erratic at doses greater than 25
mg/m2.
• Methotrexate is completely absorbed from parenteral routes.
• At conventional doses, CSF levels are only about 5%–10% of those in
plasma.
• High-dose MTX yields therapeutic concentrations in the CSF.
• Distributes into third-space fluid collections such as pleural effusion and
ascites.

50. INDICATIONS
• Breast cancer.
• Head and neck cancer.
• Osteogenic sarcoma.
• Acute lymphoblastic leukemia
• Non-hodgkin’s lymphoma
• Primary CNS lymphoma.
• Meningeal leukemia and carcinomatous meningitis.
• Bladder cancer.
• Gestational trophoblastic cancer.

51. DOSAGE RANGE
• Low dose: 10–50 mg/m2 IV every 3–4 weeks
• Low dose weekly: 25 mg/m 2 IV weekly
• Moderate dose: 100–500 m/m2 IV every 2–3 weeks
• High dose: 1–12 gm/m2 IV over a 3- to 24-hour period every 1–3 weeks
• Intrathecal (IT): 10–15 mg IT 2 times weekly until CSF is clear, then
weekly dose for 2–6 weeks, followed by monthly dose.

52. SPECIAL CONSIDERATIONS
• Methotrexate enhances the antitumor activity of 5-fluorouracil when given
24 hours before fluoropyrimidine treatment.
 Antifolate analogs ( like MTX) increase the formation of 5-FU
nucleotide metabolites when given 24 hours before 5-FU.
• Leucovorin rescues the toxic effects of methotrexate and may also impair the
antitumor activity. The active form of leucovorin is the L-isomer.
 Leucovorin is normally started 24 hours after methotrexate is
given. This delay gives the methotrexate a chance to exert its anti cancer
effects.

55. SPECIAL CONSIDERATIONS
• Thymidine—thymidine rescues the toxic effects of methotrexate and may
also impair the antitumor activity.
• Proton pump inhibitors—proton pump inhibitors may reduce the
elimination of methotrexate, which can then result in increased serum
methotrexate levels, leading to increased toxicity.
• Use with caution in patients with abnormal RFT.
• Instruct patients to stop folic acid supplements during therapy.

56. SPECIAL CONSIDERATIONS
• With high-dose therapy, methotrexate blood levels should be monitored
every 24 hours starting at 24 hours after methotrexate infusion.
• With high-dose therapy, methotrexate doses >1 grams/m2 important to
vigorously hydrate the patient with 2.5–3.5 liters/m2/day of IV 0.9%
sodium chloride starting 12 hours before and for 24–48 hours after
methotrexate infusion.
• Patients should be instructed to lie on their side for at least 1 hour after
intrathecal administration of methotrexate. This will ensure adequate
delivery of drug throughout the CSF.

57. SPECIAL CONSIDERATIONS
• Instruct patients to avoid sun exposure for at least 1 month after therapy
• Caution patients about drinking carbonated beverages as they can
increase the acidity of urine, resulting in impaired drug elimination.
• Pregnancy category D. Breastfeeding should be avoided.

58. 5-FLUOROURACIL
• TRADE NAME:- 5-FU, EFUDEX

59. ABSORPTION
• Oral absorption is variable and erratic with a bioavailability that ranges
from 40% to 70%.
• After IV administration, 5-FU is widely distributed to tissues tissues
with highest concentration in GI mucosa, bone marrow, and liver.
• Because of its extremely short half-life, on the order of 10-15 minutes,
infusional schedules of administration have been generally favored over
bolus schedules.

60. INDICATIONS:
• Colorectal cancer—adjuvant setting and advanced disease.
• Breast cancer—adjuvant setting and advanced disease.
• GI malignancies, including anal, esophageal, gastric, and pancreatic
cancer.
• Head and neck cancer.
• Hepatoma.
• Ovarian cancer.
• Topical use in basal cell cancer of skin and actinic keratoses.

61. DOSAGE RANGE
• Bolus monthly schedule: 425–450 mg/m2 IV on days 1–5 every 28
days.
• Bolus weekly schedule: 500–600 mg/m2 iv every week for 6 weeks
every 8 weeks.
• 24-hour infusion: 2400–2600 mg/m2 iv every week.
• 96-hour infusion: 800–1000 mg/m2/day iv.
• 120-hour infusion: 1000 mg/m2/day iv on days 1–5 every 21–28 days.
• Protracted continuous infusion: 200–400 mg/m2/day iv.

63. SPECIAL CONSIDERATIONS
• 5FU alone stays in the body for only a short time.
• Leucovorin can enhance the binding of fluorouracil to an enzyme
inside of the cancer cells. As a result fluorouracil may stay in the
cancer cell longer and exert its anti cancer effect on the cells
• Contraindicated in patients with bone marrow depression, poor
nutritional status, infection, active ischemic heart disease, or history
of myocardial infarction within previous 6 months.
• Monitored closely for mucositis and/or diarrhea as there is increased
potential for dehydration, fluid imbalance, and infection.
• Vistonuridine, at a dose of 10 g PO every 6 hr, may be used in
patients overdosed with 5-FU or in those who experience severe
toxicity.
• Vitamin B6 (pyridoxine 50 mg PO bid) may be used to prevent
and/or reduce the incidence and severity of hand-foot syndrome.

64. CAPECITABINE
• TRADE NAME:- XELODA

65. ABSORPTION :
• Capecitabine is readily absorbed by the GI tract.
• The rate and extent of absorption are reduced by food.
INDICATIONS
• Stage III colon cancer- XELOX(XELoda+OXaliplatin)
• Metastatic breast cancer— FDA -approved when used in combination with
docetaxel, after failure of prior anthracycline-containing chemotherapy.
• Metastatic breast cancer—FDA -approved as monotherapy in patients
refractory to both paclitaxel- and anthracycline-based chemotherapy.
• Metastatic colorectal cancer—FDA -approved as first-line therapy when
fluoropyrimidine therapy alone is preferred. XELOX combination is also FDA
proved.

66. DOSAGE RANGE
• Recommended dose for monotherapy is 1,250 mg/m2 PO BID for 2 weeks
with 1 wk rest .May decrease dose of capecitabine to 850–1,000 mg/m2
BID on days 1–14 to reduce risk of toxicity without compromising
efficacy.
• An alternative dosing schedule for monotherapy is 1,250–1,500 mg/m2
PO BID for 1 week on and 1 week off; this schedule appears to be well
tolerated, with no compromise in clinical efficacy.
• Capecitabine should be used at lower doses (850–1,000 mg/m2 bid on
days 1–14) when used in combination with other cytotoxic agents, such as
oxaliplatin and lapatinib.

67. SPECIAL CONSIDERATIONS
• Capecitabine should be taken with a glass of water within 30 minutes after a
meal.
• Contraindicated in patients with known dihydropyrimidine dehydrogenase
(DPD) deficiency-> result in a clinically dangerous increase in the anabolic
products of 5-FU.
• Patients should be monitored for diarrhea.
• Drug therapy should be stopped immediately in the presence of grades 2 to 4
hyperbilirubinemia.
• Vitamin B6 (pyridoxine 50 mg PO bid) may be used to prevent and/or reduce
the incidence and severity of hand-foot syndrome.
• Celecoxib at a dose of 200 mg PO BID may be effective in preventing and/or
reducing the incidence and severity of hand-foot syndrome.
• Diltiazem can prevent capecitabine-induced coronary vasospasm and chest
pain.

68. GEMCITABINE
• TRADE NAME:- GEMZAR

69. ABSORPTION :
• Administered by the IV route.
• Poor oral bioavailability as a result of extensive deamination within the GI tract
INDICATIONS
• Pancreatic cancer— FDA -approved as monotherapy or in combination with erlotinib for first-line
treatment of locally advanced or metastatic disease.
• Non–small cell lung cancer—FDA -approved in combination with cisplatin for first-line treatment
of inoperable, locally advanced, or metastatic disease.
• Breast cancer—FDA -approved in combination with paclitaxel for first-line treatment of metastatic
breast cancer
• Ovarian cancer—FDA -approved in combination with carboplatin for with advanced ovarian cancer
that has relapsed at least 6 months after completion of platinum-based therapy.
• Bladder cancer.
• Soft tissue sarcoma.
• Hodgkin’s lymphoma
• Non-hodgkin’s lymphoma.

70. DOSAGE RANGE
• Pancreatic cancer: 1,000 mg/m2 IV every week for 7 weeks with 1
week rest treatment then continues weekly for 3 weeks followed by 1
week off
• Bladder cancer: 1,000 mg/m2 IV on days 1, 8, and 15 every 28 days
• Non–small-cell lung cancer: 1,000-1,200 mg/m2 IV on days 1 and 8
every 21 days

71. SPECIAL CONSIDERATIONS
• Gemcitabine is a potent radiosensitizer.
• Monitor CBCS on a regular basis during therapy.
• Myelosuppression is dose-limiting.
• Pregnancy category D. Breastfeeding should be avoided.

72. OTHER USEFUL ANTI-
METABOLITES

73. OTHER USEFUL ANTI-
METABOLITES

74. THANKS