History of Chemotherapy

Era of modern chemotherapy began in early 1940s Goodman and Gilman first administered nitrogen mustard to patients with lymphoma
nitrogen mustard was developed as a war gas rather than as a medicine toxic effects on the lymphatic system led to clinical trials

 Chemotherapy attacks tumors at the cellular level by interrupting processes or inhibiting substances necessary for cellular replication and life During the cell cycle, there is replication of the entire genome and division of the cell into genetically identical daughter cells Goals of Cancer Chemotherapy Cure Prolong survival Palliation Radiosensitive

The Cell Cycle

G1 phase: cell prepares for DNA synthesis S phase: cell generates complete copy of genetic material

G2 phase: cell prepares for mitosis

M phase: replicated DNA is condensed and segregated into chromosomes G0 phase: resting state

Conventional Chemotherapy
Backbone of cancer chemotherapy regimens Cytotoxicity is not selective

Chemotherapy Classes
Alkylating agents

Anthracyclines
doxorubicin, daunorubicin nitrogen mustards idarubicin, mitoxantrone thiotepa, busulfan Antimetabolites nitrosoureas, mitomycin methotrexate procarbazine, dacarbazine purine antagonists pyrimidine antagonists

Taxanes
paclitaxel, docetaxel nab-paclitaxel

Tubulin interactive agents

vincristine, vinblastine

Topoisomerase II inhibitors
etoposide

Miscellaneous agents
bleomycin asparaginase hydroxyurea

Platinum Complexes
cisplatin, carboplatin oxaliplatin

 Chemotherapy has been applied for tx since the 1940s. Chemotherapy is tx that uses chemicals to systemically destroy the cancer. Since it is a systemic approach, there are many undersirable side effects with these drugs such as hair loss, nausea. (rapidly growing cells are first ones to go) Actions of chemotherapy relate to the cell cycle in the body. Considering that cells are the structural unit of life and are constanting divding and growing, to replace old ones. There are 5 phases in the cell cycle, G0, G1, S G2 M. G0 is the resting phase and the rest are division, synthesis, premitosis, and finally mitosis. Chemotherapy drugs fall into 2 categories, either non specific of specific. Specific drugs attack on a particular phase of the cell cycle expect the resting phase. Non specific drugs are able to attack at any phase of cell cycle.

Antimetabolite Chemotherapy Drugs

Act against metabolites, important byproducts produced from other substances in the cell during the process of metabolism Active in the production of cellular DNA Antimetabolite chemotherapy drugs work:
they take the place of an important metabolite block an enzyme that produces an important metabolite

Antimetabolite Chemotherapy Drugs

Target rapidly dividing cells, such as cancer cells, that have a high rate of metabolism Category includes:
purine analog chemotherapy drugs pyrimidine analog chemotherapy drugs folic acid blocker chemotherapy drugs

Purine Analog Chemotherapy Drugs

Purine
a molecule that forms the based upon which adenine and guanine are built two substances are important components of the DNA molecule in each cell

Analog
drug that is created by slightly modifying the molecular structure of another substance

Purine Analog Chemotherapy Drugs

Purine analog
takes the place of the purine base structure normal metabolites (adenine, guanine) cannot be built DNA cannot be produced cancer cell cannot divide

Purine Analog Chemotherapy Drugs

These drugs are used to treat different types of leukemia
cladribine (Leustatin) clofarabine (Clolar) fludarabine (Fludara) mercaptopurine (Purinethol) pentostatin (Nipent) thioguanine (Tabloid)

Pyrimidine Analog Chemotherapy Drugs

Pyrimidine
a molecule that forms the base upon which cytosine, thymine, and uracil are built (important components of DNA molecule)

Pyrimidine Analog Chemotherapy Drugs

take the place of the pyrimidine base structure normal metabolites (cytosine, thymine, uracil) cannot be built DNA cannot be produced cancer cell cannot divide

Pyrimidine Analog Chemotherapy Drugs

These drugs are used to treat many different types of cancer
capecitabine (Xeloda) cytarabine (DepoCyt, Tarabine) floxuridine (FUDR) fluorouracil (Adrucil) gemcitabine (Gemzar) troxacitabine (Troxatyl)

Folic Acid Blocker Chemotherapy Drugs

Folic acid, a B vitamin whose metabolite is important in DNA production in the cell Folic acid blocker chemotherapy drugs
act as antagonists compete with folic acid for the same enzyme, normally changes folic acid into the metabolite that carries purine to a forming DNA molecule

Folic Acid Blocker Chemotherapy Drugs

Without the folic acid metabolite
purine is not available DNA cannot be produced the cancer cell cannot divide

Folic Acid Blocker Chemotherapy Drugs

These drugs are used to treat many different types of cancer
methotrexate (Trexall) pemetrexed (Alimta) trimetrexate (Neutrexin)

The Platinums

Cisplatin Toxicity
Hematologic toxicity
can affect all 3 blood lineages minor neutropenia, thrombocytopenia, and ANEMIA its mild hematologic toxicity has allowed its combination with highly myelosuppressive chemotherapy

Ototoxicity
audiograms show bilateral and symmetrical high frequency hearing loss usually irreversible caution with other drugs (aminoglycosides)

Therapeutic indications
Cisplatin is indicated as palliative therapy, to be employed either as a single agent or in established combination therapy with other chemotherapeutic agents in the following indications: Metastatic Testicular Tumors In established combination therapy with other approved chemotherapeutic agents, in patients with metastatic testicular tumors who have already received appropriate surgical and/or radiotherapeutic procedures. Metastatic Ovarian Tumors who have already received appropriate surgical and/or radiotherapeutic procedures. An established combination consists of cisplatin and cyclophosphamide. Cisplatin, as a single agent, is indicated as secondary therapy in patients with metastatic ovarian tumors refractory to standard chemotherapy that have not previously received cisplatin therapy. Advanced Bladder Cancer Cisplatin is indicated as a single agent for patients with transitional cell bladder cancer, which is no longer amenable to local treatments such as surgery and/or radiotherapy.

Cisplatin Toxicity
Neurotoxicity
dose-limiting toxicity most common symptoms are peripheral neuropathy and hearing loss less common include Lhermittes sign (electric shock-like sensation transmitted down the spine upon neck flexion) autonomic neuropathy, seizures, encephalitic symptoms, and vestibular disturbances cumulative doses > 300 mg/m2 first signs are loss of vibration sensation, loss of ankle jerks and painful paresthesias in hands and feet proximal progression and deficits in proprioception, light touch and pain recovery is typically incomplete

Cisplatin Toxicity
Nephrotoxicity
dose-limiting toxicity renal damage is usually reversible but rarely can be irreversible and require dialysis platinum concentrations are higher in the kidney than in the plasma or other tissues initiating event is proximal tubular lesion secondary events such as disturbances in distal tubular reabsorption, renal vascular resistance, renal blood flow, and glomerular filtration, and polyuria seen 2 to 3 days later hypomagnesemia develops in about 75% of patients, beginning 3 to 12 weeks after therapy and persisting for months to years

Cisplatin Nephrotoxicity
Preventive Measures
aggressive saline hydration (enhance urinary excretion) lower doses may require less hydration infuse over 24 hours pretreatment with amifostine avoid other nephrotoxic agents magnesium supplementation predisposing factors to developing nephrotoxicity include age 60 years or older, higher doses, pretreatment GFR < 75 ml/min, cumulative dose, low albumin, single dose compared with daily x 5 administration schedules

Cisplatin Toxicity
Nausea and vomiting
acute or delayed highly emetogenic if use doses than 50 mg/m2 moderately emetogenic if use doses 50 mg/m2 severe if not adequately prevented with appropriate medications typical anti-emetic regimen
aprepitant 125 mg po day 1 then 80 mg po days 2 3 dexamethasone 12 mg po day 1 then 8 mg po daily x 3 days palonosetron 0.25 mg IVP day 1 metoclopramide 10 mg every 4 hours prn N/V

Cisplatin Administration
Mixed in 250 - 1000 ml NS Mixed with 2 4 grams magnesium sulfate in same bag Infused over atleast 2 hours Pre-hydration of 250 1000 mL NS depending on dose
ensure adequate UOP (> 200 cc/2 hours)

Caution in patients with HF or CRI who cannot tolerate this amount of fluids May require furosemide IVP Post-hydration with 1 Liter NS instruct patient to drink 6 8 full glasses of water/day (1.5 2 Liters/day) at home

Carboplatin Toxicity
Moderately emetogenic Renal impairment is rare
because it is excreted primarily in the kidneys as an unchanged drug, it is not directly toxic to the renal tubules

Neurotoxicity is rare Myelosuppression

especially THROMBOCYTOPENIA dose-limiting toxicity cumulative

Hypersensitivity reaction
thought to be due to type I hypersensitivity (IgE mediated) incidence of hypersensitivity seems to be correlated with increased number of cycles of carboplatin administered risk of hypersensitivity due to carboplatin exposure significantly increases during the sixth cycle, and it continues to increase up to cycle 8

Oxaliplatin Toxicity
Gastrointestinal Moderate emetogenicity diarrhea Minimal hematologic toxicity Thrombocytopenia is dose-related (doses > 135 mg/m2) mild neutropenia mild anemia No nephrotoxicity Hypersensitivity reaction mild generally subside upon discontinuation slowing down infusion rate and giving an antihistamine and/or steroid desensitization protocol Peripheral neuropathy Prevention: Stop and Go Strategy, Ca and Mg infusions (may compromise efficacy)

Clinical characteristics of oxaliplatin neurotoxicity

Acute symptoms Common (90% of patients) May appear at first treatment cycle Generally mild Onset during or within hours of infusion Transient, short lived Cold-triggered or cold-aggravated Dysesthesias and paresthesias Manifesting as stiffness of the hands or feet, inability to release grip, and sometimes affecting the legs or causing contractions of the jaw Distal extremeties, perioral, oral, and pharyngolaryngeal areas Depending on dosing schedule (infusion rate) Chronic symptoms 10% to 15% moderate neuropathy after a cumulative dose of 780 to 850 mg/m2 Does not seem to be schedule-dependent Dysesthesias and paresthesias persisting between cycles Progressively evolving to functional impairment: difficulties in activities requiring fine sensorimotor coordination, sensory ataxia Tends to improve/recover after treatment is stopped Spares motor neurons (like cisplatin)

Oxaliplatin Neuropathy
Supportive care for prevention of oxaliplatin induced neuropathy

avoid cold temperatures if exposure to cold temperatures cannot be avoided, such as use of the refrigerator, wear gloves during the exposure use scarves and face masks in cold weather prolonging the infusion time use cotton socks, pot holders, rubber gloves for dish washing assess the water temperature in the home use moisturizer

Comparison of Platinum Toxicity

Table 5. Comparative adverse effect profiles of platinum drugs Adverse effect Nephrotoxicity Gastrointestinal toxicity Peripheral neurotoxicity cisplatin ++ +++ carboplatin + + oxaliplatin +

+++

++

Ototoxicity
Hematologic toxicity

+
+

++

Hypersensitivity

Platinum Chemotherapy Drugs

Contain the precious metal platinum Create cross-links in DNA strands Used to treat many different types of cancer Platinum Chemotherapy Drugs carboplatin (Paraplatin) cisplatin oxaliplatin (Eloxatin)

 Platinum Coordination Complexes The platinum coordination complexes have broad antineoplastic activity and have become the foundation for treatment of ovarian, head and neck, bladder, esophagus, lung, and colon cancers. The analogs differ in their pharmacological properties, and oxaliplatin has mechanistic differences that may explain its unique activity in colorectal cancer (see "Mechanism of Action") (Dolan and Fitch, 2007). Although cisplatin and other platinum complexes do not form carbonium ion intermediates like other alkylating agents or formally alkylate DNA, they covalently bind to nucleophilic sites on DNA and share many pharmacological attributes with alkylators.

Mechanism of Action Cisplatin, carboplatin, and oxaliplatin enter cells by an active Cu2+ transporter, CTR1, and in doing so rapidly degrade the transporter (Kruh, 2003). The compounds are actively extruded from cells by ATP7A and ATP7B copper transporters and by multidrug resistance protein 1 (MRP 1); variable expression of these transporters may contribute to clinical resistance (Dolan and Fitch, 2007). Inside the cell, the chloride, cyclohexane, or oxalate ligands of the three analogs are displaced by water molecules, yielding a positively charged and highly reactive molecule. In the primary cytotoxic reaction, the aquated species of the drug then reacts with nucleophilic sites on DNA and proteins. Aquation of cisplatin is favored at the low concentrations of chloride inside the cell and in the urine. High concentrations of chloride stabilize the drug, explaining the effectiveness of chloride diuresis in preventing nephrotoxicity (see "Clinical Toxicities"). The activated platinum complexes can react with electron-rich molecules, such as sulfhydryls, and with various sites on DNA, forming both intrastrand and interstrand cross-links. The N-7 of guanine is a particularly reactive site, leading to platinum cross-links between adjacent guanines (GG intrastrand cross-links) on the same DNA strand; guanineadenine cross-links also form and may contribute to cytotoxicity. Interstrand cross-links form less frequently. DNA-platinum adducts inhibit replication and transcription, lead to single- and double-stranded breaks and miscoding, and if recognized by p53 and other checkpoint proteins, cause induction of apoptosis. Although no quantitative relationship between platinum-DNA adduct formation and efficacy has been documented, the ability of patients to form and sustain platinum adducts appears to be an important predictor of clinical response (Reed et al., 1988). The analogs differ in the conformation of their adducts and the effects of adduct on DNA structure and function. Oxaliplatin and carboplatin are slower to form adducts. The oxaliplatin adducts are bulkier and less readily repaired, create a different pattern of distortion of the DNA helix, and differ from cisplatin adducts in the pattern of hydrogen bonding to adjacent segments of DNA (Sharma et al., 2007). Unlike the other platinum analogs, oxaliplatin exhibits a cytotoxicity that does not depend on an active MMR system, which may explain its greater activity in colorectal cancer. It also seems less dependent on the presence of high mobility group (HMG) proteins that are required by the other platinum derivatives. Testicular cancers have a high concentration of HMG proteins and are quite sensitive to cisplatin. Basal-type breast cancers, such as those with BRCA1 and BRCA2 mutations, lack Her 2 amplification and hormone-receptor expression and appear to be uniquely susceptible to cisplatin through their upregulation of apoptotic pathways governed by p63 and p73 (Deyoung and Ellisen, 2007). The specificity of cisplatin with regard to phase of the cell cycle differs among cell types, although the effects of cross-linking are most pronounced during the S phase. The platinum analogs are mutagenic, teratogenic, and carcinogenic. Cisplatin- or carboplatin-based chemotherapy for ovarian cancer is associated with a 4-fold increased risk of developing secondary leukemia.

OXALIPLATIN "EBEWE" 150 MG "150 " "

Indication Oxaliplatin in combination with 5- fluorouracil and folinic acid (FA) is indicated for : * adjuvant treatment of stage III (Duke's C) colon cancer after complete resection of the primary tumour * treatment of advanced colorectal cancer.

 Oxaliplatin ) ( )!( : ( (1 ) (2

CARBOPLATIN CONCENTRATE FOR SOLUTION FOR INFUSION10MG/ML "/ "10 Indication Advanced ovarian carcinoma in initial treatment and secondary treatment. Metastatic small cell carcinoma of the lung.

ABIPLATIN 1 MG/ML "/ "1

Indication Palliative therapy to be employed either alone, or more commonly in established combination therapy with orher approved chemotherapeutic agents and in patients with metastatic testicular tumor and metastatic ovarian tumor who have alreasy received appropriate surgical and/or radiotherapeutic procedures and in patients with advanced bladder cancer.

CYMEVENE 500 MG "500

Indication Cymevene IV is indicated for the treatment of CMV retinitis in immunocompromised patiens, including patients with acquired immunodeficiency syndrome (AIDS). Cymevene IV is also indicated for the prevention of CMV disease in transplant recipients at risk for CMV disease.

IRINOTECAN
Indication Irinotecan is indicated for the treatment of patients with metastatic colorectal cancer: - in combination with 5-fluorouracil and folinic acid in patients without prior chemotherapy for metastatic disease. - as a single agent in patients who have failed an astablished 5-fluorouracil containing treatment regimen. For the treatment of patients with small cell lung cancer. For the treatment of patients with gastric cancer.

 (CPT-11) Irinotecan FU 5-

VELCADE 3.5 MG "3.5

Indication Velcade (bortezomib) for injection is indicated for the treatment of patients with multiple myeloma. Velcade (bortezomib) for injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy

GEMCITABINE MEDAC 1500 MG "1500

Indication Gemcitabine is indicated for the treatment of locally advanced or metastatic bladder cancer in combination with cisplatin. Gemcitabine is indicated for treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas. Gemcitabine, in combination with cisplatin is indicated as first line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Gemcitabine monotherapy can bee considered in elderly patients or those with performance status 2. Gemcitabine is indicated for the treatment of patients with locally advanced or metastatic epithelial ovarian carcinoma, in combination with carboplatin, in patients with relapsed disease following a recurrence-free interval of at least 6 months after platinum - based, first- line therapy. Gemcitabine in combination with paclitaxel, is indicated for the treatment of patients with unresectable, locally recurrent or metastatic breast cancer who have relapsed following adjuvant/neoadjuvant chemotherapy. Prior chemotherapy should have included an anthracycline unless clinically contraindicated

 Mechanism of Action Natural taxane, prevents depolymerization of cellular microtubules, which results in DNA, RNA, and protein synthesis inhibition

HERCEPTIN VIALS 440 MG

Indication Herceptin is indicated for the treatment of patients with metastatic breast cancer who have tumours that overexpress HER2: 1. As a single agent for the treatment of those patients who have received one or more chemotherapy regiments for their metastatic disease. 2. In combination with Paclitaxel or Docetaxel for the treatment of those patients who have not received chemotherapy for their metastatic disease. 3. Herceptin in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone-receptor positive metastatic breast cancer. Early breast cancer (EBC) : Herceptin is indicated to treat patients with HER2-positive early breast cancer following surgery and chemotherapy (neoadjuvant or adjuvant) either alone or in combination with chemotherapy excluding Anthracyclines. Herceptin should only be used in patients whose tumors have either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay. HER2 metastatic gastric cancer (mGC) Herceptin in combination with capecitabine or 5fluorouracil and cisplatin is indicated for the treatment of patients with HER2 positive metastatic adenocarcinoma of the stomach or gastro-esophageal junction who have not received prior anti-cancer treatment for their metastatic disease. Herceptin should only be used in patients with metastatic gastric cancer whose tumours have HER2 overexpression as defined by IHC2+ and a confirmatory FISH+ result, or IHC 3+, as determined by an accurate and validated assay