Chemotherapy drugs in gynecological oncology

CHEMOTHERAPY DRUGS IN GYNECOLOGICAL MALIGNANCIESALKYLATING AGENTS & PLATINUM ANALOGS

PERSPECTIVE• First anticancer molecules developed.• Family contains six major classes:•Nitrogen mustard• Aziridines• Alkyl sulfonates• Epoxides •Nitrosoureas• Triazene compounds

MAJOR CLASSES OF CLINICALLY USEFUL ALKYLATING AGENTS

CLASSES DRUGS Therapeutic Uses

Alkyl sulfonates Busulfan BMT, in CML

Ethyleneimine/ Methylmelamines

Altretamine, ThioTEPA Breast, Ovarian, Bladder Ca, BMT

Nitrogen mustards Mechlorethamine Hodgkin’s lymphoma

Melphalan Multiple myeloma & Ovarian Ca, occasionally malignant

melanoma

Chlorambucil CML

CANCER, Principles & practice of oncology, DeVita 10th ed.



Nitrogen mustards Cyclophosphamide Varieties of lymphomas, leukemias & solid tumors

Ifosfamide Testicular, breast ca, lymphoma (Non - Hodgkin); Soft tissue sarcoma; osteogenic sarcoma; lung, cervical, ovarian, bone cancer

Nitrosoureas Carmustine Glioma, glioblastoma multiforme,

medulloblastoma & astrocytoma, multiple

myelomas & lymphomasCANCER, Principles & practice of oncology, DeVita 10th ed.



Triazenes Dacarbazine Malignant melanoma & hodgkin’s lymphoma

Temozolomide Glioblastoma; astrocytoma; metastatic melanoma

Nitrosoureas Carmustine Glioma, glioblastoma multiforme,

medulloblastoma & astrocytoma, multiple

myelomas & lymphomas

Streptozotocin Cancers of islets of Langerhans CANCER, Principles & practice of oncology, DeVita 10th ed.

CLINICAL PHARMACOKINETICS/ PHARMACODYNAMICS

• Highly variable depending on individual agent• Generally have high reactivity & short half lives.• Mechlorethamine is highly unstable (Administered rapidly in a running IV

infusion to avoid rapid breakdown into inactive metabolites)• Chlorambucil & Cyclophosphamide are relatively stable, to be given orally,

and also rapidly absorbed from GI tract, whereas Melphalan has poor & variable oral absorption

• Cyclophosphamide, Ifosfamide & Dacarbazine are unusual in that they require “ACTIVATION BY CYTOCHROME P-450” in liver before they can alkylate cellular constituents.


• Major route of metabolism – spontaneous hydrolysis, although many can undergo some degree of enzymatic metabolism.

• CYCLOPHOSPHAMIDE : Activation by CYP2B6

Conversion by Aldehyde dehydrogenase

to reactive alkylating species

Detoxification through GSH conjugation reactionACROLEIN

(contributes to bladder toxicity)


• Although alkylating agents react with cells in all phases of cell cycle, their efficacy & toxicity result from interference with rapidly proliferating tissues.

• Electrophilic alkyl group or substituted group can covalently bind to cellular nucleophilic sites in DNA & RNA (amino, carboxyl, sulfhydryl, imidazole, phosphate).

• Electrophilicity is achieved through the formation of carbonium ion intermediates and can result in transition complexes with target molecules.


• Bi functional alkylating agents (with two chloro-ethyl side chains) can undergo subsequent covalent bonding with adjacent nucleophilic group, resulting in DNA-DNA or DNA – Protein cross links.

• The N-7 or O-6 positions of Guanine are particularly susceptible and may represent primary targets that determine both the cytotoxic & mutagenic properties of the therapy.

IfosfamideDose 1g/m2 , vials 1g,2g, 500mgSchedule: Day1 –to-5Mesna 200mg for 1g, 400mg for 2g of Ifosfamide, (to prevent renal endothelial damage)

AdriamycinDose: 50mg/m2 on Day 1,vials 50mg,10mg)Cost -5000/-T.Carnitor 500mg 2-2-2X3days (adriamycin to prevent cardio toxicity)Pre CT echocardiography is must for adriamycin

Ifosfamide + Adriamycin, 2nd line drugs

Gestational trophoblastic diseaseEMA-CO regimeDrugs D1 D2 D3 D4 D5 D6 D7 D8ETOPOSIDE 100mg/m2 100MG/m2

Act- D 0.5mg/m2 0.5mg/m2

Mtx 100mg/m2 IV loading dose, 200mg/m2 in 4 divide doses dilute in 5% Dx

Calcium lueucovorin

15mg 15mg

Cyclophosphamide

600mg/m2

Vincristine 1-1.5mg/m2

TOXICITIES• Primary dose-limiting toxicity - Bone marrow suppression

• Secondary limiting effect – proliferating cells of intestinal mucosa.

• CONTRAINDICATIONS: • Severely depressed bone - marrow function.• Hypersensitivity to these drugs

TOXICITIES• PRECAUTION is advised in patients with

1. Leukopenia or thrombocytopenia2. Previous exposure to chemotherapy or radiotherapy3. Tumor cell infiltration of the bone marrow4. Impaired renal or hepatic function

TOXICITIES1. Nausea & Vomiting :

frequent side effects, can be acute or delayed, Not well controlled with conventional antiemetics. Major source of discomfort & lack of compliance or even

discontinuation. Frequency & extent is highly variable among the patients and

is directly proportional to the dose of alkylating agent.

TOXICITIES2. BONE MARROW TOXICITY

• Can involve all the blood elements, leukocytes, platelets & RBCs.• Extent & time course of suppression shows marked interindividual

fluctuations. • CYCLOPHOSPHAMIDE :

• Relative platelet sparing even at very high doses (used for preparation for BMT)

• Thus, cumulative damage rarely seen when cyclophosphamide is given as single agent, and repeated high doses can be given without progressive lowering of leukocytes or platelets.

TOXICITIES2. BONE MARROW TOXICITY• CYCLOPHOSPHAMIDE :

• Relative platelet sparing even at very high doses (used for preparation for BMT)

• Thus, cumulative damage rarely seen when cyclophosphamide is given as single agent, and repeated high doses can be given without progressive lowering of leukocytes or platelets.

• Stem cell sparing property is related to the presence of high levels of Aldehyde dehydrogenase in early bone marrow precursors.

TOXICITIES3. BLADDER & RENAL TOXICITY

• HEMORRHAGIC CYSTITIS: • Unique to oxazaphosphorines i.e. Cyclophosphamide & Ifosfamide• May range from mild cystitis to severe bladder damage with massive

hemorrhage.• Due to the excretion of the toxic metabolites (ACROLEIN) in urine and

subsequent irritation of the bladder mucosa.• Adequate HYDRATION and continuous irrigationof the bladder with MESNA ( 2-

mercaptoethane sulfonate) & frequent bladder emptying can reduce the incidence & severity. (divided doses every 4hrs in 60% dose of alkylating agent)

• RENAL TOXICITY : nitrosoureas at high cumulative doses.

TOXICITIES4. INTERSTITIAL PNEUMONITIS & PULMONARY TOXICITY• Busulfan therapy (long term )• Cyclophosphamide in cumulative doses exceeding

1000mg/m2 may lead to pneumonitis like symptoms.• Other agents like Melphalan, Chlorambucil & Mitomycin C

can lead to pulmonary fibrosis after therapy.• Direct cytotoxicity to the pulmonary epithelium resulting in

alveolitis & fibrosis.

TOXICITIES5. GONADAL TOXICITY, TERATOGENESIS & CARCINOGENESIS

• Have profound effect on reproductive tissues.• In women, high incidence of amenorrhoea & ovarian atrophy associated with

cyclophosphamide or melphalan therapy.Lancet 1972;1(7762):1212–1214

• AGE related : develops after low doses in older compared with younger patients and less likely to be reversible in the older cohort.

• PATHOLOGICAL ANALYSIS: absent of mature & primordial follicles, • ENDOCRINOLOGY :

• ↓estrogen & progesterone levels • ↑FSH & LH levels.

•


• All are teratogenic and carcinogenic due to the DNA damaging properties.

• 1ST Trimester administration – definitive risk of malformation in the fetus.• 2nd & 3rd TM administration does not increase the risk of fetal

malformations above normal.Nicholson HO. Cytotoxic drugs in pregnancy: review of reported cases.

J Obstet Gynaecol Br Commonw 1968;75(3):307–312

• Development of second malignancy as a consequence of alkylating therapy – Fulminant


• Development of second malignancy as a consequence of alkylating therapy – Fulminant acute myeloid leukemia is found in patients treated with Melphalan, Cyclophosphamide (much less leukemogenic than Melphalan), Chlorambucil and the Nitrosoureas.

Lancet 1972;1(7762):1212–1214

• Rate of acute leukemia in patients with ovarian cancer treated with alkylating agents who survive 10 years might be as high as 10%.

• Acute leukemia- the most frequent malignancy usually develops 1-4years after exposure to the drug.

Reimer RR, Hoover R, Fraumeni JF Jr, et al.

Acute leukemia after alkylating-agent therapy of ovarian cancer. N Engl J Med 1977;297(4): 177–181

TOXICITIES6. ALOPECIA

• After cyclophosphamide administration is quite severe specially when in used in combination with vincristine or doxorubicin.

• Regrowth of hair occurs after the cessation of the therapy but may have changes in color and greater curl.

7. ALLERGIC REACTIONS

TOXICITIES7. ALLERGIC REACTIONS

• Bind covalently to proteins → can act as haptens and produce allergic reactions.

8. IMMUNOSUPPRESSION• Cyclophosphamide the most immunosuppressive. • Sustained drug treatments can lead to profound immunosuppresion and

increases fungal, viral and protozoal infections.1. Selective suppression of B-lymphocytes function2. Depletion of B-lymphocytes3. Suppression of functions mediated by T-lymphocytes such as GVHR and

delayed hypersensitivity.

DRUG RESISTANCE AND MODULATION

• Intrinsic and acquired resistance occurs, limiting the therapeutic utility

• As alkylating agents have narrow therapeutic index, the emergence of resistance can have significant clinical impact on clinical success.

• Factors that contribute to resistance include1. Alteration in the drug uptake or transport.2. Increased repair of drug induced nucleic acids damage.3. Failure to activate the alkylating pro-drugs4. Increased scavenging of the drug species5. Increased non-enzymatic detoxification 6. Altered expression of genes coding for the cellular commitment to apoptosis.

CHEMOTHERAPY DRUGS IN GYNECOLOGICAL MALIGNANCIESPLATINUM ANALOGS

INTRODUCTION

• Alone or in combination with other chemotherapeutic agents, cis-diamminedichloroplatinum (II) (cisplatin) and its analogs have made a significant impact on the treatment of a variety of solid tumors for nearly 40 years.

• Two other platinum complexes are currently approved for use in the United States:• cisdiamminecyclobutanedicarboxylate platinum (II) (carboplatin) and• 1,2-diaminocyclohexaneoxalato platinum (II) (oxaliplatin).

INTRODUCTION• Other analogs with unique activities are in various stages of clinical

development,• nedaplatin (Japan) and • lobaplatin (China) are locally registered.

HISTORY

• The realization that platinum complexes exhibited antitumor activity began serendipitously in a series of experiments to investigate the effect of electromagnetic radiation on the growth of bacteria, carried out by Dr. Barnett Rosenberg and colleagues beginning in 1961.

• Exposure of the bacteria to an electric field resulted in a profound change in their morphology; this effect was found not to be from the electric field, but from electrolysis products produced by the platinum electrodes.

PLATINUM CHEMISTRY• Platinum exists primarily in either a 2+ or 4+ oxidation state.

• These oxidation states dictate the stereochemistry of the ligands surrounding the platinum atom.

• Platinum (II) compounds exhibit a square planar geometry, in which the • ammine ligands (also called carrier groups) are relatively stable, • whereas the opposite, more polar ligands (leaving groups) are more easily

displaced and so confer reactivity toward charged macromolecules, including DNA.

CHEMISTRY

MECHANISM OF ACTION1. DNA Adduct Formation :

• Cisplatin and its analogs react preferentially at the N7 position of guanine and adenine residues to form a variety of monofunctional and bifunctional adducts

• predominant lesions are d( GpG )Pt intrastrand cross-links.

• Adducts impede certain cellular processes that require the separation of both DNA strands, such as replication and transcription (may contribute to the drug’s cytotoxicity)

MECHANISM OF ACTION

• Carboplatin - adducts are essentially the same as those of cisplatin; however, higher concentrations of carboplatin are required (20- to 40-fold for cells) to obtain equivalent total platinum-DNA adduct levels due to its slower rate of aquation.

• Oxaliplatin intrastrand adducts form even more slowly due to a slower rate of conversion from monoadducts; however, they are formed at similar DNA sequences and regions as cisplatin adducts

MECHANISM OF ACTION2. DNA interstrand cross links:

• Although the DNA adducts are well-recognized to result in G-G interstrand cross-links, like classical alkylating agents,

• Platinum drugs have the capacity to form intrastrand cross-links, albeit to a lesser degree.

• Intrastrand cross-links are highly cytotoxic.

CELLULAR RESPONSES TO PLATINUM INDUCED DNA DAMAGE

DNA replicatio

n on a damaged template

Binding of platinum-

DNA damage

recognition proteins

( High-mobility group

proteins HMG1 and

HMG2 )

DNA Damage

Signalling (signaling

through the JNK pathway,

and inhibition at the level of JNK seems especially relevant to platinum

drug cytotoxicity in vitro and

in vivo)

MECHANISM OF RESISTANCE

MECHANISM OF RESISTANCE• Currently described mechanisms of platinum drug resistance include

1. Reduced cellular accumulation

2. Intracellular detoxification [(glutathione (GSH) and larger proteins as exemplified by metallothionein (MT)]

3. Repair of Pt-DNA lesions [nucleotide excision repair (NER), with a role for MMR]

4. Increased damage tolerance, and the 5. Autophagy (represents a regulated dissolution of cellular elements into a

characteristic set of subcellular organelles detectable by electron microscopy and linked by a particular profile of gene expression changes.)

CLINICAL PHARMACOLOGY & PHARMACOKINETICS

CLINICAL PHARMACOLOGY

• Pharmacokinetic differences observed between platinum drugs may be attributed to the structure of their leaving groups.

• Complexes containing leaving groups that are less easily displaced exhibit reduced plasma protein binding, longer plasma half-lives, and higher rates of renal clearance.

CISPLATIN • After intravenous infusion, cisplatin rapidly diffuses into tissues and is

covalently bound to plasma protein.

• More than 90% of platinum is bound to plasma protein at 4 hours after infusion.

• The disappearance of ultrafilterable platinum is rapid and occurs in a biphasic fashion.

• Half-lives of 10 to 30 minutes and 0.7 to 0.8 hours have been reported for the initial and terminal phases, respectively.

CISPLATIN

• Cisplatin excretion is dependent on renal function, which accounts for the majority of its elimination.

• The percentage of platinum excreted in the urine has been reported to be between 23% and 40% at 24 hours after infusion. Only a small percentage of the total platinum is excreted in the bile.

CARBOPLATIN • The differences in pharmacokinetics observed between cisplatin and

carboplatin depend primarily on the slower rate of conversion of carboplatin to a reactive species.

• Thus, the stability of carboplatin results in a low incidence of nephrotoxicity.

CARBOPLATIN • Carboplatin diffuses rapidly into tissues after infusion; however, it is considerably

more stable in plasma. Only 24% of a dose was bound to plasma protein at 4 hours after infusion.

• The disappearance of platinum from plasma after short intravenous infusions of carboplatin has been reported to occur in a biphasic or triphasic manner.

• The half-lives for total platinum range from 12 to 98 minutes during the first phase (T1/2α) and from 1.3 to 1.7 hours during the second phase (T1/2β). Halflives reported for the terminal phase range from 8.2 to 40 hours.

• The disappearance of ultrafilterable platinum is biphasic with T1/2α and T1/2β values ranging from 7.6 to 87 minutes and 1.7 to 5.9 hours, respectively.

CARBOPLATIN• Carboplatin is excreted predominantly by the kidneys, and cumulative

urinary excretion of platinum is 54% to 82%, most as unmodified carboplatin. The renal clearance of carboplatin is closely correlated with the glomerular filtration rate (GFR).

• This observation enabled Calvert et al. to design a carboplatin-dosing formula based on the individual patient’s GFR.

DRUG ADMINISTRATION

CISPLATIN• Administered in a chloride-containing solution intravenously over 0.5 to 2.0 hours.

• To minimize the risk of nephrotoxicity, patients are pre-hydrated with at least 500 mL of salt-containing fluid. Immediately before cisplatin administration, mannitol (12.5 to 25.0 g) is given parenterally to maximize urine flow.

• A diuretic such as furosemide may be used also, along with parenteral antiemetics (dexamethasone together with a 5-hydroxytryptamine (5-HT3) antagonist)

• A minimum of 1 L of post-hydration fluid is usually given. The intensity of hydration varies somewhat with the dose of cisplatin.

CISPLATIN• Cisplatin may also be administered regionally to increase local drug exposure

and diminish side effects. • Intraperitoneal use was defined by Ozols et al. and by Howell and colleagues. • Measured drug exposure in the peritoneal cavity is some 50-fold higher

compared to levels achieved with intravenous administration. • At standard dosages in ovarian cancer patients with low-volume disease, a

randomized intergroup trial suggested that intraperitoneal administration is superior to intravenous cisplatin in combination with intravenous cyclophosphamide.

• The development of combinations of carboplatin and paclitaxel has, however, superseded this technique in the treatment of ovarian cancer, and the intraperitoneal route is now infrequently used.

CARBOPLATIN

• Carboplatin is reconstituted in chloride-free solutions (unlike cisplatin, because chloride can displace the leaving groups) and

• Administered over 30 minutes as a rapid intravenous infusion.

• Extensive hydration is not required because of the lack of nephrotoxicity at standard dosages.

OXALIPLATIN • Uncomplicated in its clinical administration.• For bolus infusion, the required dose is administered in 500 mL of chloride-free

diluent over a period of 2 hours. • Oxaliplatin is most frequently given as a single dose every 2 weeks (85

mg/m2) or every 3 weeks (130 mg/m2), alone or with other active agents. • It is common to pretreat patients with active antiemetics, such as a 5-HT3

antagonist, but the nausea is not as severe as with cisplatin. • No prehydration is required. • relatively low incidence of myelosuppression, • the predominant toxicity is cumulative neurotoxicity. The development of

an oropharyngeal dysesthesia, often precipitated by exposure to cold, may require prolonging the duration of administration to 6 hours.

• On occasion, the occurrence of hypersensitivity also requires slowing the infusion.

DRUG TOXICITY

DRUG TOXICITY – PLATINUM COMPOUNDS

CISPLATIN• The side effects associated with cisplatin (at single doses of more than 50 mg/m2)

include • Nausea and vomiting, • Nephrotoxicity, • Ototoxicity, • Neuropathy, and • Myelosuppression.

• Rare effects include visual impairment, seizures, arrhythmias, acute ischemic vascular events, glucose intolerance, and pancreatitis.

CISPLATIN

• Nausea & vomiting

• The nausea and vomiting stimulated a search for new antiemetics.

• These effects are currently best managed with 5-HT3 antagonists, usually given with a glucocorticoid, although other combinations of agents are still widely used.

• In the weeks after treatment, continuous antiemetic therapy may be required.

CISPLATIN• Nephrotoxicity

• is ameliorated but not completely prevented by hydration. • The renal damage to both glomeruli and tubules is cumulative, and

• After cisplatin treatment, serum creatinine levels are no longer a reliable guide to GFR.

• An acute elevation of serum creatinine level may follow a cisplatin dose, but this index returns to normal with time.

• Tubule damage may be reflected in a salt-losing syndrome that also resolves with time.

CISPLATIN• Ototoxicity • Ototoxicity is a cumulative and irreversible side effect (results from damage

to the inner ear) • The initial audiographic manifestation is loss of high-frequency acuity (4,000• to 8,000 Hz). • When acuity is affected in the range of speech, cisplatin should be

discontinued under most circumstances and carboplatin substituted where appropriate.

• Peripheral neuropathy is also cumulative, although less common than with agents such as vinca alkaloids.

• This neuropathy is usually reversible, although recovery is often slow.

CARBOPLATIN

• Myelosuppression, is the dose-limiting toxicity of carboplatin.

• most toxic to the platelet precursors, but neutropenia and anemia are frequently observed.

• The lowest platelet counts after a single dose of carboplatin are observed 17 to 21 days later, and recovery usually occurs by day 28.

• The effect is dose dependent, but individuals vary widely in their susceptibility

CARBOPLATIN• Nausea and vomiting, although frequent, are

• less severe,

• shorter in duration, and

• more easily controlled with standard antiemetics (i.e., prochlorperazine[Compazine]), dexamethasone, lorazepam) than that after cisplatin treatment.

• Renal impairment is infrequent,

• Alopecia is common, especially with the paclitaxel-containing combinations.

• Neurotoxicity is also less common than with cisplatin, although it is observed more frequently with the increasing use of high-dose regimens.

• Ototoxicity is also less common.

CHEMOTHERAPY DRUGS IN GYNECOLOGICAL MALIGNANCIESANTIMETABOLITES

CLASSIFICATIONANTIMETABOLITES

Anti- folates ( Methotrexate, Permetrexed, Pralatrexate)

5-Flouropyramidines (5-Flourouracil)CapecitabineCytarabine Gemcitabine

6-Thiopurines (6-Mercaptopurine [6-MP], 6-Thioguanine[6-TG])

Fludarabine. Cladribine, Clofarabine

ANTIFOLATES – MECHANISM OF ACTION

• Antifolates - tight-binding inhibitors of DHFR (a key enzyme in folate metabolism)

• DHFR - maintains the intracellular folate pools in their fully reduced form as tetrahydrofolates, and

• These compounds serve as “one-carbon” carriers required for the synthesis of thymidylate, purine nucleotides, and certain amino acids.

MECHANISM OF ACTION• The cytotoxic effects of MTX, Permetrexed, and Pralatrexate are mediated by their respective polyglutamate metabolites.

• These metabolites exhibit• prolonged intracellular half-lives – allowing for prolonged drug action in tumor cells.• potent, direct inhibitors of several folate-dependent enzymes, including DHFR, TS, AICAR formyltransferase and GAR formyltransferase

METHOTREXATE• Aminopterin was the first antimetabolite with documented clinical activity in the treatment of children with acute leukemia in the 1940s.

• Subsequently replaced by Methotrexate (MTX), the 4-amino, 10-methyl analog of folic acid, which remains the most widely used antifolate analog, with activity against a wide range of cancers

METHOTREXATE• It is used in treatment of cancer, autoimmune diseases, ectopic

pregnancy, and for the induction of medical abortions.

• Methotrexate began to replace the more toxic antifolate Aminopterin starting in the 1950s.

• The drug was originally synthesized by the Indian biochemist Yellapragada Subbarow and clinically developed by the American paediatrician Sidney Farber.

• It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.

INDICATIONS

• Non-Hodgkin’s lymphoma

• Primary CNS lymphoma

• Acute lymphoblastic

• Leukemia

• Breast cancer

• Bladder cancer

• Osteogenic sarcoma

• Gestational trophoblastic cancer

PHARMACOKINETICS• Oral bioavailability – erratic & saturable (at >25mg/m2 )

• Completely absorbed from parenteral routes, peak serum concentration in 30 – 60 minutes.

• Distributes into third-space fluid collections (pleural effusions and ascitic fluid)

• Prolongs the terminal half-life of the drug, leading to potentially increased clinical toxicity.

PHARMACOKINETICS• Main route of drug elimination – Renal excretion

(glomerular filtration and tubular secretion).

• About 80% to 90% of an administered dose is eliminated unchanged in the urine within 24hrs.

• Doses of MTX, therefore, should be reduced in proportion to reductions in creatinine clearance.

• Renal excretion of MTX is inhibited by probenecid, penicillins, cephalosporins, aspirin, and nonsteroidal anti-inflammatory drugs

MECHANISM OF RESISTANCE• Alteration in antifolate transport because of either a defect in the reduced folate carrier or folate receptor systems.

• Decreased formation of polyglutamates through either • Decreased expression of FPGS or • Increased expression of gamma - glutamyl hydrolase.

• Alterations in the target enzymes DHFR and/or TS through increased expression of wild-type protein or overexpression of a mutant protein with reduced binding affinity for the antifolate.

MECHANISM OF RESISTANCE• Alterations in the target enzymes DHFR and/or TS• through increased expression of wild-type protein (Gene amplification) or• overexpression of a mutant protein with reduced binding affinity for the antifolate.

DOSAGE• Low dose: 10–50 mg/m2 IV every 3–4 weeks• Low dose weekly: 25 mg/m2 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

Intramuscular Methotrexate Regimens for Treatment of Low-Risk GTNFrequency Dose Population

StudiedCR Rate (%) First Author

Weekly 30–50 mg/m2 Nonmetastatic GTN

74–81 Homesley, 1988

Days 1,3,5,7 50 mg/d Low-risk GTN 67–72 McNeish, 2002

Khan, 20035-Day 0.4 mg/kg/d Low-risk GTN

(majority)60 Soper, 1994a

CR = clinical remission (calculated for first-line treatment without needing alternative chemotherapy)GTN = gestational trophoblastic neoplasia.

Gestational trophoblastic diseaseEMA-CO regimeDrugs D1 D2 D3 D4 D5 D6 D7 D8ETOPOSIDE

100mg/m2 100MG/m2

Act- D 0.5mg/m2 0.5mg/m2

Mtx 100mg/m2 IV loading dose, 200mg/m2 in 4 divide doses dilute in 5% Dx

Calcium lueucovorin

15mg 15mg

Cyclophosphamide

600mg/m2

Vincristine 1-1.5mg/m2

TOXICITY1. Myelosupression : (dose limiting) leucocyte

nadir at day 4-7 & recovery by day 14.

2. Gastrointestinal: • Mucositis – onset typically 3-7days after

Methotrexate therapy.• Nausea & vomitting are dose dependent.

TOXICITY3. Renal failure : Intra-tubular precipitation of MTX &

its metabolites.• ARF, azotemia, urinary retention, & uric acid

nephropathy

4. Hepatotoxicity: transient elevation of transaminases & bilirubin with high doses.

5. Pneumonitis: fever, cough & intestitial pulmonary infiltrates.

TOXICITY6. Arachnoiditis: severe headaches, nuchal rigidity, seizures,

vomiting, fever & inflammatory cell infiltrate in CSF after IT administration.

7. Acute cerebral dysfunction: 5-15% receiving high dose methotrexate- paresis, aphasia, behavioral abnormalities & seizures.

8. Skin toxicity: erythematous skin rashes, pruritis, urticaria, photosensitivity,& hyperpigmentation. Radiation recall syndrome

TOXICITY6. Menstrual irregularities, abortion & fetal

death.

5-FLUOROURACIL• 5-FU and its derivatives are an integral part of treatment for a

broad range of solid tumors including • GI malignancies (esophageal, gastric, pancreatic, colorectal,

anal, and hepatocellular cancers), • breast, • head and neck, and • skin cancers.

• It continues to serve as the main backbone for combination regimens used to treat metastatic colorectal cancer (mCRC) and as adjuvant therapy of early-stage colon cancer.

MECHANISM OF ACTION1. The inhibition of Thymidylate Synthase,

2. Incorporation into RNA, and

3. Incorporation into DNA

4. Genotoxic stress resulting from TS inhibition may also activate programmed cell-death pathways in susceptible cells, which leads to the induction of parental DNA fragmentation

MECHANISM OF RESISTANCE1. Increased expression of thymidylate synthase

2. Decreased levels of folate substrate for Thymidylate Synthase reaction.

3. Decreased incorporation into RNA & DNA.

4. Increased activity of DNA Repair enzymes (uracil glycosylase & dUTPase).

5. Increased salvage of physiologic nucleosides including thymidine.

6. Alteration in thymidylate synthase with decreased binding affinity of enzyme for FdUMP.

PHARMACOKINETICS• Oral bioavailability – erratic & variable (ranges from 40 – 70%).

• After intravenous bolus doses, metabolic elimination is rapid, with a half-life of 8 to 14 minutes.

• More than 85% of an administered dose of 5-FU is enzymatically inactivated by DPD (Dihydropyramidine Dehydrogenase), the rate-limiting enzyme in the catabolism of 5-FU.

PHARMACOKINETICS• A pharmacogenetic syndrome has been identified in which partial

or compete deficiency in the DPD enzyme is present in 3% to 5%

and 0.1% of the general population, respectively.

• can result in a clinically dangerous increase in the anabolic products of 5-FU.

• DPD deficiency do not manifest a phenotype only until they are treated with 5-FU, and

• they can develop severe GI toxicity in the form of mucositis and/or diarrhea, myelosuppression, neurologic toxicity, and in rare cases, death.

DRUG INTERACTIONS1. Leucovorin : enhances toxicity & antitumor activity of 5FU

when given in sequence first.

• Stabilises the TS-FdUMP reduced folate complex resulting in maximal inhibition of thymidylate synthase.

2. Methotrexate: increases the formation of 5FU nucleotide metabolites when given 24hrs before 5FU

3. Thymidine & Uridine : rescue against DNA & RNA mediated host toxicities.

TOXICITY• The spectrum of 5-FU toxicity is dose- and schedule-dependent

• The main side effects are diarrhea, mucositis, and myelosuppression.

• The dermatologic HFS (palmar - plantar erythrodysesthesia) is more commonly observed with infusional 5-FU therapy. • Tingling, numbness, pain, erythema, dryness, rash, swelling , increased

pigmentation, nail changes, pruritis of hands & feet &/or desquamation.

TOXICITY• Acute neurologic symptoms have also been reported, and

they include somnolence, cerebellar ataxia, and upper motor signs.

• Treatment with 5-FU can, on rare occasions, cause coronary vasospasm, resulting in a syndrome of chest pain, cardiac enzyme elevations, and electrocardiographic changes. Cardiac toxicity seems to be related more to infusional 5-FU than bolus administration.

TOXICITY

CANCER, Principles & practice of oncology, DeVita 10th ed.

GEMCITABINE• Gemcitabine (2′,2′-difluorodeoxycytidine) is a

difluorinated deoxycytidine analog.

• This compound has significant clinical activity against several human solid tumors, including • pancreatic, bile duct, gall bladder, • small cell and non–small-cell lung, • bladder, • ovary, and breast cancers as well as • Hematologic malignancies, namely Hodgkin’s and non-

Hodgkin’s lymphoma

MECHANISM OF ACTION• Nucleoside Transporter system.

• Activation to active triphosphate metabolite (dFdCTP).

• Incorporation into DNA.

• Inhibition of DNA synthesis and function

PHARMACOKINETICS• Poor oral bioavailability (due to excessive deamination in GI tract).

• Deamination occurs in liver, plasma & peripheral tissues.

• Enzyme : Deoxycytidine deaminase.

• Short infusion times <70mins- half life 30-90mins.

• Infusion times >70mins – half life is 4 – 10 hrs.

• Clearance – dependent on age & gender.• 30% lower clearance in women & elderly.

• Negligible plasma proteins binding.

DRUG INTERACTIONS• Cisplatin & Etoposide : increase Gemcitabine toxicity.

• Also is a potent radio sensitizer.

TOXICITY• Gemcitabine is a relatively well-tolerated drug when used as a

single agent.

• The main dose-limiting toxicity is myelosuppression, with neutropenia more commonly experienced than thrombocytopenia.

• Toxicity is schedule dependent, with longer infusions producing greater hematologic toxicity.

• Transient flulike symptoms, including fever, headache, arthralgias, and myalgias, occur in 45% of patients.

• Asthenia and transient transaminasemia may occur.• Renal microangiopathy syndromes, including hemolytic-uremic

syndrome and thrombotic thrombocytopenic purpura, have been reported rarely.

TOXICITY• Nausea & vomiting (mild to moderate) - in 70% patients.

• Diarrhoea &/or mucositis – in 15-20% patients

• Transient flulike symptoms, including fever, headache, arthralgias, and myalgias, occur in 45% of patients.

• Infusion reactions : flushing, facial swelling, headache dyspnoea or chest pain (usually related to the rate of infusion)

• Asthenia and transient transaminasemia may occur.

• Renal microangiopathy syndromes, including hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura, have been reported rarely.

• Alopecia rare.

CHEMOTHERAPY DRUGS IN GYNECOLOGICAL MALIGNANCIESANTIMICROTUBULE AGENTS

MICROTUBULES

• Vital and dynamic cytoskeletal polymers that play a critical role in cell division, signaling, vesicle transport, shape, and polarity.

• Composed of 13 linear protofilaments of polymerized α/β-tubulin heterodimers arranged in parallel around a cylindrical axis

• Associated with regulatory proteins such as microtubule-associated proteins, tau, and motor proteins kinesin and dynein.

MICROTUBULES• The specific biologic functions of microtubules are due to their unique

polymerization dynamics.

• Tubulin polymerization is mediated by a nucleation-elongation mechanism.

• One end of the microtubules, termed the plus end, is kinetically more

dynamic than the other end, termed the minus end

MICROTUBULES• Antimicrotubule agents are tubulin-binding drugs that

• directly bind tubules, • inhibitors of tubulin-associated scaffold kinases, or • inhibitors of their associated mitotic motor proteins to, (ultimately, disrupt

microtubule dynamics)

• They are broadly classified (according to their effects on tubulin polymerization) as • microtubule stabilizing• microtubule destabilizing agents

MICROTUBULES

ANTI-MICROTUBULE AGENTS• TAXANES : Paclitaxel, Docetaxel, Cabazitaxel, Tesetaxel

• VINCA ALKALOIDS: Vincristine, Vinblastine, Vinorelbine, Vinflunine

• MICROTUBULE ANTAGONISTS: Estramustine Phosphate, Epothilones, Maytansinoids and Auristatins: DM1, MMAE

• MITOTIC MOTOR PROTEIN INHIBITORS: Aurora Kinase and Pololike Kinase Inhibitors

TAXANES

TAXANES• The first-in-class microtubule stabilizing drugs.

• Bark extract of the Pacific yew tree, Taxus brevifolia.

• Paclitaxel was identified as the active constituent with a report of its activity in carcinoma cell lines in 1971.

• Motivation to identify taxanes derived from the more abundant and available needles of Taxus baccata led to the development of Docetaxel, which is synthesized by the addition of a side chain to 10-deacetylbaccatin III, an inactive taxane precursor.

MECHANISM OF ACTION1. Cell cycle-specific, active in mitotic (M) phase of the cell

cycle.

2. High affinity binding to microtubule enhances the tubular polymerization

Normal dynamic process of microtubule network is inhibited

Inhibition of mitosis & cell division.

PACLITAXEL • Poorly soluble and not orally bioavailable.

• Distributes widely to all body tissues (including third space fluid collections).

• >90 % plasma and cellular protein binding.

• Metabolised extensively by hepatic cytochrome p450 microsomal system.

• Approximately 71% of an administered dose is excreted in the stool (majority as metabolites , <10% as parent form)

PACLITAXEL • Dosage 135-175mg/m2 IV as a 3hour infusion.every three

weeks in ovarian ca.

• Weekly schedule: 80-100mg/m2 IV each week for 3weeks & 1week rest.

• Also a radiosensitizing agent.

PACLITAXEL • DRUG PREPARATION:

• Poorly soluble in water .• Is formulated in polyoxyethylated castor oil (Cremaphor EL) and

dehydrated alcohol.• Dilute in 5% dextrose or 0.9% NS to a final conc. Of 0.3 to 0.12mg/ml• Reconstituted vials are stable in room temperature for up to 27 hours.• Always administered in glass or polyolefin containers using 0.22μm

filter and polyethylene lined sets.• CAUTION: NOT TO USE PVC CONTAINERS OR TUBINGS (Crem EL causes

leaching into infusion fluid).

NANOPARTICLE ALBUMIN-BOUND PACLITAXEL

• solvent-free colloidal suspension made by homogenizing paclitaxel with 3% to 4% albumin under high pressure

• form nanoparticles of ∼130 nm that disperse in plasma to ∼10 nm.• Improved responses when compared to solvent based paclitaxel,

are not fully understood.

NANOPARTICLE ALBUMIN-BOUND PACLITAXEL

• an improved pharmacokinetic profile • with a larger volume of distribution and

• a higher maximal concentration of circulating, unbound, free drug. (nab-paclitaxel achieves 33% higher drug concentration over CrEL-paclitaxel)

• improved tumor accumulation by the • enhanced permeability and retention (EPR) effect; and • receptor-mediated transcytosis via an albumin-specific receptor (gp60) for

endothelial transcytosis and• binding of secreted protein acidic and rich in cysteine (SPARC) in the tumor

interstitium

DRUG INTERACTIONS1. Sequence-dependent pharmacokinetic and toxicologic

interactions• Cisplatin & carboplatin – inhibit plasma clearance of paclitaxel -

myelosupression is greater. ( Always PACLITAXEL must be given FIRST ).

• Adriamycin - paclitaxel reduces plasma clearance of doxorubicin by 30-35% - increased severity of myelosupression.

• Agents that inhibit cytochrome P-450 mixed-function oxidases interfere with the metabolism of paclitaxel and docetaxel.• Phenytoin, phenobarbital – accelerate the metabolism.

TOXICITY1. HYPERSENSITIVITY REACTIONS (HSR):

• CrEL causes hypersensitivity reactions.• Occurs in 20-40% patients.• major reactions usually occurring within the first 10 minutes after

the first treatment and resolving completely after stopping the treatment.

• All patients should be premedicated with steroids, diphenhydramine, and an H2 antagonist,

• although up to 3% will still have reactions. • Nab paclitaxel: Hypersensitivity reactions have not been observed

during the infusion period and, therefore, steroid premedications are not necessary.

TOXICITY2. NEUROPATHY:

• Principle toxicity.• Dose dependent effect.• Presents in a symmetric stocking glove distribution, at first transient

and then persistent.• A neurologic examination reveals sensory loss, and • Neurophysiologic studies reveal axonal degeneration and

demyelination.• Risk factors : longer infusions and dose >175mg/m2, DM, Chronic

alcoholism, prior exposure to known neurotoxic agents (e.g. cisplatin).

TOXICITY3. MYELOSUPPRESION:

• Neutropenia is noncumulative.• onset is usually on days 8 to 11, and recovery is generally

complete by days 15 to 21.

4. TRANSIENT BRADYCARDIA: • In 30% patients.• Routine cardiac monitoring not required.

5. ALOPECIA: • Nearly in all patients

• reversible loss of total body hair.

TOXICITY6. NAIL DISORDERS:

• Observed in those receiving >6weekly courses, not seen with 3week schedule.

• ridging, nail bed pigmentation, onychorrhexis, and onycholysis.

7. GI TOXICITY: • In 30% -40% patients – mucositis &/or diarrhoea.• Mucositis more common with 24hr schedule.• Mild to moderate nausea – usually for brief duration.

DOCETAXEL• A semisynthetic taxane.

• Derived from needles of Taxus baccata

• Which is synthesized by the addition of a side chain to 10-deacetylbaccatin III, an inactive taxane precursor.

• Cell cycle specific agent.

• Docetaxel came off patent in 2010 and a generic form is available.

DOCETAXEL• Not administered orally.

• Distributes widely to all body tissues.

• Extensive protein binding >90%.

• Extensively metabolised by hepatic p450 microsomal system.

• About 75% excreated via fecal elimination.

• Renal clearance minor (<10%).

• Terminal half life – 11hrs.

DOCETAXEL• DRUG PREPARATION: • Formulated in Polysorbate 80, less allergic than Cremaphor

EL.• Unopened vials require protection from bright light.• Use only glass, polypropylene or polyolefin plastic (bags)

IV containers.• Reconstituted vials are stable for 8hrs at room

temperature.

DOCETAXEL – DRUG INTERACTIONS• Acts as a radiosensitizing agent.

• Agents that inhibit cytochrome P-450 mixed-function oxidases interfere with the metabolism of docetaxel.• E.g. cyclosporine, ketoconazole, erythromycin.

TOXICITY1. NEUTROPENIA:

• Dose-limiting toxicity.• onset is usually noted on day 8, with complete resolution by

days 15 to 21. • Neutropenia is significantly less when low doses are

administered weekly.

TOXICITY2. HYPERSENSITIVITY REACTIONS (HSR):

• Severe reactions in <5% of patients.• Generalised skin rash, erythema, hypotension, dyspnoea,

&/or bronchospasm.• Usually within 2-3minutes of infusions and frequently

observed with first or second treatment.• can usually be reinstituted without sequelae after treatment

with diphenhydramine and an H2-receptor antagonist.

TOXICITY3. FLUID RETENTION SYNDROME:

• characterized by edema, weight gain, and third-space fluid collection. • is cumulative and is due to increased capillary permeability.• Increased incidence in total doses >400mg/m2.• Occurs in about 50% patients.• Prophylactic treatment with corticosteroids has been

demonstrated to reduce the incidence of fluid retention.

TOXICITY4. ALOPECIA: • In up to 80%patients.

5. SKIN CHANGES:• Occur in as many as 50% to 75% of patients.• Maculo-papular skin rash & dry, itchy skin (commonly

forearm & hands).• Brown discoloration of fingernails may occur.• Hand – foot syndrome also described.

TOXICITY6. MUCOSITIS/DIARRHOEA:

• 40% patients• Mild to moderate nausea & vomiting (usually brief duration)

7. PERIPHERAL NEUROPATHY:• Less commonly observed than with paclitaxel.• Mainly sensory neuropathy.

8. ASTHENIA :• a prominent complaint in patients who have been treated

with large cumulative doses.

• Docetaxel has a different toxicity profile to paclitaxel and appears to be equivalent to paclitaxel when combined with carboplatin.

• The Scottish Gynaecological Cancer Trials Group (SCOT-ROC) study randomly assigned 1,077 women with stages IC to IV epithelial ovarian cancer to carboplatin with either paclitaxel or docetaxel (307).

• The efficacy of docetaxel was similar to paclitaxel: The median PFS was 15.1 months versus 15.4 months, and the docetaxel group had less extremity weakness, sensory peripheral neuropathy, arthralgias, and myalgias than the paclitaxel group.

• However, the docetaxel plus carboplatin regimen was associated with significantly more myelosuppression and febrile neutropenia (11% compared to 2%).

• Docetaxel is not commonly used, but is a reasonable substitute for paclitaxel in patients who are at greater risk of neuropathy or who have an allergic reaction to paclitaxel.

VINCA ALKALOIDS - VINCRISTINE• Plant alkaloid derived from Catharanthus roseus.

• Inhibits tubulin polymerization , disrupting the formation of microtubule assembly during mitosis.

• May also inhibit DNA, RNA, & protein synthesis.

VINCA ALKALOIDS - VINCRISTINE• Administered only by IV route.

• Not available for oral use.

• Widely & rapidly distributed into body tissues within 30 mins of administration.

• Poor penetration into BBB.

• Metabolised by liver Cyt P450 microsomal system.

• Majority (80%) is excreted in bile & feces. 15-20% recovered in urine.

• Terminal half life is long ˜ 85hrs.

VINCA ALKALOIDS - VINCRISTINE• Dosage: 1mg/m2 IV PUSH .

• Vials should be refrigerated until use.

DRUG INTERACTIONS• Used with caution in patients receiving medications that inhibit drug

metabolism via hepatic cytochrome P450 system.

• PHENYTOIN : – levels are reduced& also its subsequent efficacy by VCR.

• DIGOXIN :- VCR Reduces the blood levels & efficacy.

• CISPLATIN & PACLITAXEL : - concurrent administration may increase the risk & severity of Neurotoxicity.

• METHOTREXATE :- VCR increases the uptake of MTX resulting in enhanced antitumor activity & host toxicity.

TOXICITY• NEUROTOXICITY:• Most common dose- limiting toxicity.• Clinical manifestations – peripheral neuropathy

(paresthesias, paralysis & loss of deep tendon reflexes)• ANS dysfunction (orthostasis, sphincter problems &

paralytic ileus)• Cranial nerve palsies, ataxia, cortical blindness, seizures,

& coma

TOXICITY• VESICANT:

• Extravasation may cause local tissue injury, inflammation & necrosis.•Vein should be adequately flushed after treatment. • If extravasation is suspected, treatment should be discontinued, aspiration of any residual drug remaining in the tissues should be attempted, and

TOXICITY• Prompt application of heat (not ice) for 1 hour four times daily

for 3 to 5 days can limit tissue damage.• Hyaluronidase, 150 to 1,500 U (15 U/mL in 6 mL 0.9% sodium

chloride solution) subcutaneously, through six clockwise injections in a circumferential manner using a 25-gauge needle (changing the needle with each new injection) into the surrounding tissues may minimize discomfort and latent cellulitis.• A surgical consultation for early debridement – recommended.

TOXICITY• GI SYMPTOMS :-• Constipation, abdominal pain & paralytic ileus

• ALOPECIA (20%), SKIN RASH & FEVER:-

• SIADH (Syndrome of inappropriate secretion of antidiuretic

hormone) : and patients who are receiving intensive hydration are particularly prone to severe hyponatremia secondary to SIADH.

DRUG RESISTANCE• Alteration in tubulin with decreased affinity for drugs.

• MDR-I phenotype with increased expression of P170 glycoprotein.• Results in enhanced drug efflux with decreased intracellular

accumulation of the drug.

• The overexpression of stathmin, a destabilizing protein, has been reported to decrease sensitivity to paclitaxel and vinblastine.

• Loss of BRCA1 (Tumor suppressor gene) can lead to impaired taxane- induced activation of apoptosis due to microtubules that are more dynamic and less susceptible to taxane-induced stabilization and proximity-induced activation of caspase-8 signaling

CHEMOTHERAPY DRUGS IN GYNECOLOGICAL MALIGNANCIESTOPOISOMERASE INHIBITORS

• Topoisomerases fulfill the need for cellular DNA to be densely packaged in the cell nucleus, transcribed, replicated, and evenly distributed between daughter cells following replication without tangles.

• They prevent and resolve DNA and RNA entanglements and resolve DNA supercoiling during transcription and replication.

Classification of Human Topoisomerases and Topoisomerase Inhibitors

Type Polarity Mechanism Protein Main Functions

Drugs

IA 3’PY Rotation/swiveling

Top1, Top1mt

DNA supercoiling relaxation,replication,

and transcription

Camptothecins Noncamptothecins

IIA 5’PY Strand passageATPase

Top2α Decatenation/

replication

Anthracyclines,AnthracenedionesEpipodophyllotox-insTop2β Transcription

IB 5’PY Strand passage

Top3α DNA replication None

Top3β RNA topoisomeras

e

• Topoisomerases solve DNA topologic problems by cutting the DNA backbone and religating without the assistance of any additional ligase.

Top1 and Top1mt are the simplest, nicking/closing, and relaxing DNA as monomers in the absence of cofactor, and even at ice temperature.

Top2 enzymes, on the other hand, are the most complex Topoisomerases working as dimers, requiring ATP binding and hydrolysis, and divalent metal (Mg2+) for catalysis.

Top3 enzymes also require Mg2+ for catalysis but function as monomers without ATP requirement

TOPOISOMERASE I INHIBITOR : CAMPTOTHECINS

• Topotecan (Hycamtin)

• Irinotecan (Camptosar)

TOPOTECAN• Semisynthetic derivative of Camptothecins, an alkaloidextract

from Camptothecata acuminata tree.

• Inhibits topoisomerase I function.

• Binds to stabilizes the topI & DNA complexes and prevents the religation of the DNA after it has been cleaved by Top1.

• The collision between this stable cleavage complex and the advancing replicating fork results in double strand DNA breaks & cellular death.

TOPOTECAN• Administered only by IV route.

• Widely distributes in body tissues. Plasma protein binding (10%-35%).

• Peak drug levels achieved within 1hour after drug administration.

• Metabolism: rapid conversion in plasma & in aqueous solution from lactone ring to carboxylate form.

• Major route of elimination is RENAL (40%-68%)

• Elimination half life – approx 3hrs.

TOPOTECAN

• Dosage : 1.5mg/m2 IV for five consecutive days given every 3weekly.

• Indications: 1. Ovarian Ca – FDA approved in patients with advanced ovarian

cancer who failed platinum based chemotherapy.

2. Small cell lung ca.

3. AML

• TOXICITY: myelosuppression is dose limiting.

TOPOTECANTOXICITY: 1. Myelosuppression is dose limiting. Neutropenia commonly observed.

2. Nausea & vomiting (mild – moderate & dose related), occur in 60% - 80%.

3. Diarrhoea also observed.

4. Headache, fever, malaise, myalgias.

5. Microscopic hematuria (10%).

6. Alopecia

7. Transient elevation in serum transaminases.

TOPOTECAN• Topotecan is an active second-line treatment for patients

with platinum-sensitive and platinum-resistant ovarian disease.

• The predominant toxicity of topotecan is hematologic, especially neutropenia. With the 5-day dosing schedule, 70–80% of patients have severe neutropenia, and 25% have febrile neutropenia, with or without infection.

TOPOTECAN• In some studies, regimens of 5 days produce better response rates

than regimens of shorter duration, but in others, reducing the dose to 1 mg/m2/d for 3 days is associated with similar response rates but lower toxicity.

Rodriguez et al. Gynecol Oncol. 2001;83:257–262Gronlund et al. Cancer. 2002;95:1656–1662

• In a study of 31 patients, one-half of whom were platinum refractory, topotecan 2 mg/m2/d for 3 days every 21 days had a 32% response rate.

Brown et al. Gynecol Oncol. 2003;88:136–140

TOPOTECAN• Weekly topotecan administered at a dose of 4 mg/m2/wk for 3

weeks with a week off every month produced a response rate similar to the 5-day regimen with considerably less toxicity.

• Therefore, this is now considered the regimen of choice for this agent.

Homesley et al.A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer

patients. Gynecol Oncol. 2001;83:394–399.

TOPOISOMERASE II INHIBITORS

1. DNA INTERCALATORS • Anthracyclines- Doxorubicin, lip-doxorubicin,

daunorubicin, epirubicin, idarubicin.• Anthracenediones- Mitoxantrone.• Antibiotics – Dactinomycin

2. NONINTERCALATORS:• Epipodophyllotoxins – Etoposide, Teniposide.

DOXORUBICIN (ADRIAMYCIN)• Anthracyclines are natural products derived from Streptomyces peucetius variation caesius.

• They were found to target Top2 well after their clinical approval.

MECHANISM OF ACTION• Intercalates into DNA resulting in inhibition of DNA

synthesis & function.

• Inhibits transcription through inhibition of DNA-dependent RNA polymerase.

• Inhibits topII by forming cleavage complexes with DNA & TopII to create uncompensated DNA helix torsional tension, leading to eventual DNA breaks.

• Formation of cytologic oxygen free radicals result in single - & double stranded DNA breaks with subsequent inhibition of DNA synthesis & function.

INDICATIONS• FDA-labeled indications for standard doxorubicin include

• acute lymphocytic leukemia (ALL), AML, chronic lymphoid leukemia,

• Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma,

• multiple myeloma, • Ovarian cancer• Mycosis fungoides, • Kaposi sarcoma, • Breast cancer (adjuvant therapy and advanced), • advanced prostate cancer, advanced gastric cancer,• Ewing sarcoma, • Thyroid cancer,

INDICATIONS• Advanced neuroblastoma, • advanced non–small-cell lung cancer, • advanced ovarian cancer, • advanced transitional cell bladder cancer,• cervical cancer, and • Langerhans cell tumors.

• Doxorubicin has activity in other malignancies as well, including • soft tissue sarcoma, osteosarcoma, • carcinoid, and • liver cancer

DOXORUBICIN• Not absorbed orally.

• 70-80% of drug & its metabolites are plasma protein bound.

• Metabolised extensively in liver to hydroxylated metabolite, doxorubicinol

• 40-50% is excreted via biliary system.

• Less than 10% by kidneys.

• Terminal half life is prolonged i.e 20-48hrs.

• Typically administered at a recommended dose of 30 to 75 mg/m2 every 3 weeks intravenously.

DOXORUBICINDRUG INTERACTIONS:

1. Dexamethasone, heparin, 5FU – incompatible with Doxorubicin – concurrent use may lead to precipitation.

2. Dexrazoxane – (iron-chelating agent) inhibits the cardiotoxic effects.

3. Cyclophosphamide – increased risk of hemorrhagic cystitis &cardiotoxicity.

4. Phenobarbital, phenytoin – Increased plasma clearance of doxorubicin.

5. Herceptin, mitomycin C – increased risk of cardiotoxicity.

6. Digoxin – Doxorubicin decreases the oral bioavailability.

7. 6-Mercaptopurine – increased hepatotoxicity.

TOXICITY1. Myelosuppression: Dose limiting, Leukopenia more

common2. Nausea & Vomiting: usually mild, in 50%of patients.3. Mucositis & Diarrhoea: 4. Cardiotoxicity: Acute & Chronic5. Strong Vesicant6. Hyperpigmentation of nails, skin rash & urticaria.

Radiation recall syndrome, hypersensitivity to sunlight.7. Alopecia - universal but reversible within 3months8. Red orange discoloration of urine9. Allergic hypersensitivity reactions- rare

CARDIOTOXICITY• Anthracyclines are responsible for cardiac toxicities, and

special considerations are necessary to minimize this severe side effect.

• Acute doxorubicin cardiotoxicity

• is reversible, and • clinical signs include tachycardia, hypotension,

electrocardiogram changes, and arrhythmias.

• It develops during or within days of anthracycline infusion, and its incidence can be significantly reduced by slowing doxorubicin infusion rates.

CARDIOTOXICITY• Chronic and delayed cardiotoxicity

• more common and

• More severe (irreversible).

• Chronic cardiotoxicity with congestive heart failure peaks at 1 to 3 months but can occur even years after therapy.

• Myocardial damage has been shown to occur by several mechanisms.

1. The classical mechanism – direct generation of reactive oxygen species (ROS) during the electron transfer from the semiquinone to quinone moieties of the anthracycline.

2. A recent study has also related doxorubicin cardiotoxicity to the poisoning of Top2β cleavage complexes in myocardiocytes.

CARDIOTOXICITY• The mechanism of anthracycline CM is not fully elucidated, but there

is emerging evidence that cardiomyocyte apoptosis may play a major role.

• The production of free radicals generated during cardiomyocyte metabolism of the anthracycline results• in membrane lipid peroxidation, with the consequent • activation of the extrinsic and intrinsic apoptotic pathways.

• It is thought that free radicals are generated • by enzymatic reduction of the anthracycline quinone ring and • by formation of iron-anthracycline complexes.

• The intrinsic antioxidant defense of the cardiomyocyte is more limited than other organs, leading to its apparent selective toxicity profile.

CARDIOTOXICITY• PATHOLOGY :

• Endomyocardial biopsy is characterized by a predominant finding of • multifocal areas of patchy and interstitial fibrosis (stellate

scars) and • occasional vacuolated myocardial cells (Adria cells).

• Myocyte hypertrophy and degeneration,

• Loss of cross-striations, and the

• Absence of myocarditis are also characteristic of this diagnosis.

CARDIOTOXICITY• The delayed CM presents as fatigue, dyspnea on exertion, orthopnea

with sinus tachycardia, S3 gallop, pedal edema, pleural effusions, and elevated jugular venous distention.

• Nevertheless, these classic clinical features of NICM are often late manifestations.

• In order to reduce the incidence and/or severity of delayed CM, keen clinical recognition of factors that may lead toward a NICM include • monitoring cumulative dose (CD) of agent used,

• early detection strategies,

• limiting total cumulative dose, and

• the timely use of adjunctive cardioprotective agents or modified infusional or pegylated regimens/drugs are important.

CARDIOTOXICITY• The risk of anthracycline CM depends on CD received.

• Historically, a 5% risk is seen at• 400 to 450 mg/m2 for doxorubicin,• 900 mg/m2 for daunorubicin, • 800 to 935 mg/m2 for epirubicin, and • 223 mg/m2 for idarubicin.

• Cofactors for cardiotoxic risk include • mediastinal irradiation, which includes the heart,

• Older (particularly >70 years) or younger (<15 years) age,

• known coronary artery disease,

• antecedent valvular disease, and

• hypertension.

CARDIOTOXICITY• DIAGNOSIS:

• Generally made by comparing serial left ventricular function studies.

• Several modalities can be employed including • multigated radionuclide imaging,

• two-dimensional transthoracic echocardiography, and

• cardiac magnetic resonance imaging (cMRI).

• Regardless of the modality employed, a left ventricular ejection fraction (LVEF) of ≥50% is considered within normal range.

• A low LVEF regardless of symptom burden remains a contraindication for anthracycline use.

CARDIOTOXICITY

• The electrocardiogram (ECG) findings associated with anthracycline-induced CM include • sinus tachycardia, • low voltage, poor R-wave progression, and • nonspecific T-wave changes.

• Even sinus tachycardia alone is a relatively late finding, such that

• Serial ECGs are of little value in early detection.

CARDIOTOXICITY• In two small prospective studies of transthoracic echocardiogram and

cMRI, both modalities reported that it was possible to distinguish patients who had developed CM from others by LVEF measures at baseline and at 200 to 300 mg/m2

• of doxorubicin.

• A fall of ≥10% at 200 mg/m2 had 72% specificity and 90% sensitivity in detecting later CD.

• At a dose of 300 mg/m2, 50% had developed a change in LVEF >10% with 25% of patients with evidence of myocardial structure changes.

Lunning, et al. Cardiac magnetic resonance imaging for the assessment of the myocardium after

doxorubicin-based chemotherapy.Am J Clin Oncol 2013

CARDIOTOXICITYOTHER MODALITIES:

• Serological markers: Brain Natriuretic Peptide, Cardiac troponin T Levels

• Percutaneous endomyocardial biopsy of the right ventricle.

CARDIOTOXICITY• The management of anthracycline-induced CM is similar to

other causes of NICM.

• Angiotensin-converting enzyme inhibitors, β-blockers, and diuretics are commonly used.

• These agents do not cure or permanently control the CM.

• Rather, the CM may become progressive despite these agents after more than 5 years.

• The only curative therapy remains cardiac transplantation.

CARDIOTOXICITYCARDIOPROTECTION: • The iron-chelating cardioprotectant dexrazoxane decreases the risk

of clinical CM in patients who have received doxorubicin doses of ≥300 mg/m2. • The American Society of Clinical Oncology recommends the use of

dexrazoxane in this setting. • However, American Society of Clinical Oncology guidelines do not

advocate dexrazoxane in the several important situations including • adjuvant regimens, CD <300 mg/m2, • pediatric patients, • or in high-risk diseasepatients.

• Clinical data are also insufficient to recommend dexrazoxane with other anthracyclines, except epirubicin in metastatic breast cancer.

CARDIOTOXICITY• Aside from early detection, other strategies to reduce the

incidence of CM are • the use of low-dose or infusional drug schedules in an attempt

to reduce peak drug dose delivery, and• the use of liposomal formulations.

• Liposomal formulations have been shown to permit higher CD and lower CM at the same dose

LIPOSOMAL DOXORUBICIN• Liposomal doxorubicin (Doxil in the United States and Caelyx in

Europe) has activity in platinum- and taxane-refractory disease.

• Doxorubicin is also available in a polyethylene glycol (PEG)ylated liposomal form, which allows for enhancement of drug delivery.

• Additionally, liposomal doxorubicin produces less nausea and vomiting and relatively mild myelosuppression compared to doxorubicin.

• Use of liposomal doxorubicin has been associated with less cardiotoxicity

• even at doses exceeding 500 mg/m2.

LIPOSOMAL DOXORUBICIN• Liposomal doxorubicin does not cause neurologic toxicity or

alopecia. • Its predominant severe toxicity is the hand–foot syndrome, also

known as palmar–plantar erythrodysesthesia or acral erythema, which is observed in 20% of patients who receive 50 mg/m2 every 4 weeks.• It is administered every 4 weeks, which makes it convenient, and it

is relatively well tolerated at the lower dose of 40 mg/m2, which is widely used. • In a study of 89 patients with platinum-refractory disease, including

82 paclitaxel-resistant patients, liposomal doxorubicin (50 mg/m2 every 3 weeks) produced a response in 17% (one complete and 14 partial responses) .

Gordon et al, Gynecol Oncol. 2004;95(1):1–8.

LIPOSOMAL DOXORUBICIN• There have been two randomized trials comparing liposomal doxorubicin with

either topotecan or paclitaxel.

• In a study of 237 women who relapsed after receiving one platinum-containing regimen, 117 of whom (49.4%) had platinum-refractory disease, liposomal doxorubicin 50 mg/m2 over1 hour every 4 weeks was compared with topotecan 1.5 mg/m2/d for 5 days every 3 weeks.

Gordon et al, Gynecol Oncol. 2004;95(1):1–8Gordon et al , J Clin Oncol. 2001;19:3312–3322.

• The two treatments had a similar overall response rate (20% vs. 17%), time to progression (22 vs. 20 weeks), and median overall survival (66 vs. 56 weeks).

• The myelotoxicity was significantly lower in the liposomal doxorubicin– treated patients.

LIPOSOMAL DOXORUBICIN• In a second study comparing liposomal doxorubicin with single-

agent paclitaxel in 214 platinumtreated patients who had not received prior taxanes, the overall response rates for liposomal doxorubicin and paclitaxel were 18% and 22%, respectively, and median survivals were 46 and 56 weeks, respectively. Neither was significantly different.

Smith et al. Ann Oncol. 2002;13:1590–1597.

• In practice, most patients are treated with a starting dose of 40 mg/m2 of liposomal doxorubicin every 4 weeks.

DACTINOMYCIN• Dactinomycin was the first antibiotic shown to have

antitumor activity

• Product of Streptomyces species.

• Consists of tricyclic phenoxazone ring attached to two peptide side chains.

• This unique structure allows for tight intercalation into DNA between adjacent guanine–cytosine bases, leading to Top2 and Top1 poisoning and transcription inhibition.

DACTINOMYCIN• Poor oral bioavailability & administered only via IV route.

• After an IV administration – rapidly dissappears from circulation within 2minutes.

• Concentrates in nucleated blood cells.

• Does not cross BBB.

• Highly plasma protein bound.

DACTINOMYCIN• Dactinomycin is FDA approved for • Ewing sarcoma, • Gestational trophoblastic neoplasm,

• Metastatic nonseminomatous testicular cancer,• Nephroblastoma, and • Rhabdomyosarcoma.

DACTINOMYCIN• Act-D can be given every other week is a 5-day regimen or

in a pulsed fashion.

• MTX can be given similarly in a 5-day regimen, weekly in a pulsed fashion, or over 8 days alternating with folinic acid (a.k.a. calcium leucovorin).

• No study has compared all of these protocols with regard to success and morbidity.

DACTINOMYCIN• The GOG performed a prospective randomized study of pulsed Act-

D versus weekly pulsed MTX and reported that pulsed Act-D had a significantly higher remission rate in patients with low-risk GTN.

• Shah et al. found that the 8-day MTX-folinic acid (MTX-FA) regimen was more cost-effective than the biweekly pulsed administration of Act-D.

• The selection of chemotherapy should be influenced by the associated systemic toxicity.

DACTINOMYCIN• DOSAGE :

• 12μg/kg per day for 5days biweekly .

• 1.25mg/m2 pulsed therapy 2weekly.

DACTINOMYCIN• If the response to two consecutive courses of MTX-FA is

inadequate, the patient is considered to be resistant to MTX, and Act-D should be promptly substituted in patients with nonmetastatic and low-risk metastatic GTN.

• If the hCG levels do not decline by 1 log after a course of Act-D, the patient should be considered resistant to Act-D as a single agent, and dose-intensive therapy with combination chemotherapy should be started.

DACTINOMYCIN• TOXICITIES:

• Myelosuppression,

• Veno - occlusive disease of the liver,

• Nausea, vomiting,

• Alopecia,

• Erythema, and acne.

• Additionally, similar to doxorubicin, dactinomycin can cause radiation recall and severe tissue necrosis in cases of extravasation.

TOPOISOMERASE II INHIBITORS

1. DNA INTERCALATORS • Anthracyclines- Doxorubicin, lip-doxorubicin,

daunorubicin, epirubicin, idarubicin.• Anthracenediones- Mitoxantrone.• Antibiotics – Dactinomycin

2. NONINTERCALATORS:• Epipodophyllotoxins – Etoposide, Teniposide.

EPIPODOPHYLLOTOXINS

• Epipodophyllotoxins are glycoside derivatives of podophyllotoxin,

• An antimicrotubule agent extracted from the Podphyllum peltatum mandrake plant.

• Two derivatives, demethylated on the pendant ring, etoposide and teniposide were shown to primarily function as Top2 poisons rather than through antimicrotubule mechanisms.

ETOPOSIDE• Cell cycle specific agent with activity in late S & G2 phase.

• Inhibits topoisomerase II by stabilizing the topoisomerase II-DNA complex and preventing the unwinding of DNA.

• Bioavailability of oral capsules is approximately 50% (requires double dosing of an IV dose).

• However oral absorption is non-linear & decreases with higher doses (>200mg).

ETOPOSIDE• Large fraction plasma protein bound (90-95%).

• Metabolised primarily by liver via glucoronidation to hydroxy acid metabolites, which are less active than parent compounds.

• 30-50% excreted in urine, and about 2-6% in stool via biliary excretion.

• Elimination half life ranges from 3 – 10 hrs.

ETOPOSIDE• INDICATIONS:

• Germ cell tumors

• Small & Non-small cell lung cancer

• Hodgkin’s lymphoma & NHL

• Gastric cancer

• High dose therapy in transplant setting for various malignancies, including breast cancer, lymphoma and ovarian cancer

ETOPOSIDE• DRUG INTERACTIONS :

• Warfarin : etoposide may alter the anticoagulation effect of warfarin by prolonging PT & INR.

• Coagulation parameters need to be monitored and dose of warfarin may require adjustment.

TOXICITY1. Myelosuppression: Dose limiting, Leukopenia more common2. Nausea & Vomiting: usually mild to moderate, in30 - 40%of

patients.3. Allergic hypersensitivity reactions- chills, fever.

Bronchospasm, dyspnoea, facial & tongue swelling & hypotension. (<2% patients)

4. Alopecia – in nearly two thirds of the patients5. Mucositis & Diarrhoea: unusual with standard doses but

seen with high doses in transplant settings.6. Anorexia, metallic taste during infusion, local inflammatory

reaction at injection site.7. Radiation recall skin changes.8. Increased second malignancy: AML, associated with 11:23

translocation, within 5 – 8 years of treatment.

TOXICITY• The chance of developing treatment-related leukemia following

etoposide is dose related. • The incidence of leukemia is approximately 0.4–0.5% (representing a

30-fold increased likelihood) in patients receiving a cumulative etoposide dose of less than 2,000 mg/m2 compared with as much as 5% (representing a 336-fold increased likelihood) in those receiving more than 2,000 mg/m2.

Schneider et al. Acute myelogenous leukemia after treatment for malignant germ cell tumors in children.

J Clin Oncol. 1999;17:3226–3233.Kollmannsberger et al.

Secondary leukemia following high cumulative doses of etoposide in patients treated for advanced germ cell tumors.

J Clin Oncol. 1998;16:3386–3391.

CHEMOTHERAPY DRUGS IN GYNECOLOGICAL MALIGNANCIESANTI TUMOUR ANTIBIOTICS

BLEOMYCIN• Bleomycin is a glycopeptide antibiotic

• produced by the bacterium Streptomyces verticillus.

• Small peptide with a molecular weight of 1500

• Contains a DNA binding region and an iron binding region at opposite ends of molecule.

• Iron is necessary as a cofactor for free radical generation and bleomycin cytoxic activity.

BLEOMYCIN• The exact mechanism for DNA strand scission has been

suggested to be due to bleomycin’s chelating of metal ions (primarily iron) and producing a pseudoenzyme that reacts with oxygen to produce superoxide- and hydroxide-free radicals, thus cleaving DNA.

BLEOMYCIN• Oral bioavailability is poor.

• When administered in intra-pleural space for malignant effusion. Approx. 45-50% absorbed into systemic circulation.

• Distributes into extra & intra cellular fluid.

• Less than 10% is protein bound.

BLEOMYCIN• After IV administration rapid biphasic disappearance from

circulation.

• Terminal half life - 3hrs

• Rapidly inactivated in tissues (liver & kidney) by bleomycin hydrolase.

• Eliminated primarily by kidneys (50-70% of given dose excreted unchanged in urine).

• Thus, needs dose reduction in renal dysfunction.

BLEOMYCININDICATIONS:

• Germ cell tumors

• Hodgkin’s and non-hodgkin’s lymphoma

• Head & neck cancers

• Squamous cell ca of skin cervix & vulva.

• Sclerosing agent for malignant pleural effusion & ascites.

BLEOMYCINDOSAGE:

• Germ cell tumors : 30 Units IV on DAY 2, 9 & 16 every 21days as a part of BEP regime.

• Intracavitary instillation into pleural space : 60units.

BLEOMYCINDRUG INTERACTIONS:

1. OXYGEN: High conc. May enhance the pulmonary toxicity. FiO2 must not be higher than 25% when possible.

2. PHENOTHIAZINES: enhance the activity of bleomycin by competing with liver P450 enzymes.

3. CISPLATIN: decreases renal clearance of bleomycin.

4. RADIATION THERAPY: enhances pulmonary toxicity of bleomycin.

BLEOMYCINTOXICITY:

1. SKIN REACTIONS: Most common side effects & include • Erythema, hyperpigmentation of skin, striae &

vesiculations.• Skin peeling , thickening of skin& nail beds,

hyperkeratosis & ulceration can also occur.• Usually occur in second & third week after treatment.• When cumulative doses has reached 150-200units

BLEOMYCIN2. HYPERSENSITIVITY REACTIONS: • In the form of fever & chills.• Observed in upto 25% of patients.• True anaphylactoid reactions are rare but more common

in patients with lymphoma

BLEOMYCIN2. HYPERSENSITIVITY REACTIONS: • In the form of fever & chills.• Observed in upto 25% of patients.• True anaphylactoid reactions are rare but more common

in patients with lymphoma

3. MYELOSUPPRESSION : relatively mild

4. VASCULAR EVENTS – MI, stroke & raynaud’s phenomenon, rarely reported.

BLEOMYCIN5. PULMONARY TOXICITY :• Dose limiting toxicity.• occurs in 10% of patients, and is dependent on the

cumulative dose.• The risk increases in patients older than 70 years and

in those who receive a total cumulative dose greater than 400 U.

BLEOMYCIN5. PULMONARY TOXICITY : Other risk factors include• underlying lung disease, • prior irradiation to the chest or mediastinum, and • exposure to high concentrations of inspired oxygen are

at increased risk. • Increased use of granulocyte colony-stimulating factor

(G-CSF)

BLEOMYCIN & G-CSF• The exacerbating effects of G-CSFs seem to be associated with a

marked infiltration of activated neutrophils along with the lung injury caused by the direct effects of bleomycin.

Azulay et al. Effect of granulocyte colony-stimulating factor on bleomycin-induced acute lung injury and

pulmonary fibrosis. Crit Care Med 2003;31:1442–1448.

Adachi et al. Effects of granulocyte colony-stimulating factor on the kinetics of inflammatory cells in the

peripheral blood and pulmonary lesions during the development of bleomycin-induced lung injury in rats.

Exp Toxicol Pathol 2003;55:21–32.

BLEOMYCIN & G-CSF• In a retrospective review, 18% of a total of 141 patients with

Hodgkin lymphoma treated with a bleomycin-containing regimen developed pulmonary toxicity.

• G-CSF use was one of the key factors associated with the development of this complication, and omission of bleomycin had no impact on clinical outcomes.

Martin et al. Bleomycin pulmonary toxicity has a negative impact on the outcome of patients with

Hodgkin’s lymphoma. J Clin Oncol 2005;23:7614–7620.

BLEOMYCIN • Clinically, may present with cough, dyspnea, dry inspiratory

crackles, and infiltrates on chest radiograph.

• Pulmonary function testing is the most sensitive approach to monitor patients, and

• Pulmonary function tests should be obtained at baseline and before each cycle of therapy, with a specific focus on the

• carbon monoxide diffusion capacity and

• vital capacity.

BLEOMYCIN • A decrease greater than 15% in either diffusion capacity of

carbon monoxide or vital capacity should mandate immediate discontinuation of bleomycin.

THANK YOU

Chemotherapy drugs in gynecological oncology

Health & Medicine

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