1. PHARMACOTHERAPY III PHCY 510
University of Nizwa
College of Pharmacy and Nursing
School of Pharmacy
PHARMACOTHERAPY III
PHCY 510
Lecture 13 Neoplastic Disorders “Malignancy & Chemotherapy” Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy, CPN University of Nizwa

2. Cancer (neoplasm, tumor, or malignancy) is not a single disease.
Group of diseases characterized by uncontrolled growth and spread of abnormal cells.
Cancer cells do not respond to normal processes that regulate cell growth, proliferation, and survival.
They cannot carry out the physiologic functions of their normal differentiated (mature) counterparts.
Other characteristics of cancer cells include their ability to invade adjacent normal tissues and break away from the primary tumor (metastasize) and travel through the blood or lymph to establish new tumors (metastases) at a distant site.

3. They stimulate formation of new blood vessels (angiogenesis) and have endless replication potential and continue to grow and survive.
Cancers can arise in any tissue in the body and may be classified as benign or malignant.
If malignant, cancer cells are allowed to grow uncontrollably, results in the death of patient.
If benign cancer cells cannot spread by tissue invasion or metastasize.

4. Etiology
Cancers arise from the transformation of a single normal cell.
An initial “event” causes damage or mutation to the cell’s DNA.
These events may include
lifestyle
environmental
occupational factors
some medical therapies (e.g., cytotoxic chemotherapy, immunosuppressive therapy, or radiation therapy)
hereditary factors
Currently, cigarette smoking is maybe the most significant single factor that contributes to development of cancers.

5. Pathogenesis
Two gene classes, oncogenes and tumor-suppressor genes, play a major role in the pathogenesis of cancer.
Damage to cellular DNA can result in mutations that lead to the development of oncogenes and loss or inactivation of tumor suppressor genes.
Tumor-suppressor genes are normal genes that encode for proteins that suppress in appropriate cell division or growth.
Oncogenes are genes whose over activity or presence in certain forms can lead to the development of cancer.

6. Some types of malignancies:
Carcinoma: Cancers resulting from epithelial cells. This includes breast, prostate, lung, pancreas, and colon.
Sarcoma: Cancers arising from connective tissue (i.e. bone, cartilage, fat, nerve), originating outside the bone marrow.
Lymphoma and leukemia: Arise from hematopoietic (blood-forming) cells that leave the marrow and mature in the lymph nodes and blood
Germ cell tumor: Cancers derived from pluripotent cells, most often presenting in the testicle or the ovary.

7. Screening and Early Detection
Standardized screening tests can help identify disease in asymptomatic individuals (screening)
or help diagnose a disease in symptomatic individuals (early detection).
Histologic diagnosis of a tumor is the most important determinant of how a malignancy will be treated.
A surgical biopsy or excision of the primary tumor, followed by a microscopic and a biochemical evaluation by a pathologist, can provide the most accurate histologic diagnosis.
Staging is the process that determines the extent or spread of the disease.

8. Clinical Presentation
Initial signs and symptoms of malignant disease are variable.
Depend on the histologic diagnosis, the location (including metastases), and the size of the tumor.
Pain secondary to compression, obstruction, and destruction of adjacent tissues and organs is the most common presenting symptom.
Other common initial symptoms reported by patients with cancer include anorexia, weight loss, and fatigue.

9. Treatment
Surgery
Oldest modality available to treat patients with cancer.
A significant role in preventing (e.g., removal of colonic polyps or cervical dysplasia), diagnosing, and staging various cancers (e.g., biopsy for histologic evaluation).
Surgery can also be used to manage cases of both localized and advanced tumors.
Patients with metastatic disease also can have surgery to relieve pain or improve functional abnormalities caused by the advanced tumor (e.g., gastrointestinal obstruction).

10. Radiation Therapy
Used to eradicate localized tumor masses.
Not all cancers are sensitive to the lethal effects of radiation. Hence it has limited application.
Radiation therapy could encompass a wider area around the tumor and remove the tumor from regions of the body where surgery cannot safely reach.
Radiation therapy also can be used when surgery could result in considerable disability or disfigurement.
Not all cancers can be cured by surgery or radiation therapy. Systemic treatments, including chemotherapy, endocrine therapy, signal transduction pathway inhibitors, biologic response modifiers are preferred for patients to free of disease.

11. Chemotherapy Cytotoxic Chemotherapy
Traced to World War II, when an explosion of mustard gas produced bone marrow and lymphoid hypoplasia in sea men exposed to the gas.
Lead to use of alkylating agents (derivatives of mustard gas) in the treatment of Hodgkin disease and other lymphomas.

12. Cytotoxic Drugs
Cytotoxic drugs have both anti-cancer cells activity and the potential to damage normal cells.
Chemotherapy may be given to cure the cancer, to prolong life, or to palliate symptoms.
Chemotherapy may be combined with radiotherapy or surgery or both as adjuvant treatment

13. Alkylating Agents
They act by damaging DNA, thus interfering with cell replication.
Prolonged usage can severely affect the reproductive system (sterility) and may cause acute leukaemias.
Examples: Cyclophosphamide Chlorambucil, Melphalan Busulfan. In treatment of leukemia

14. Antimetabolites
Combine irreversibly with vital cellular enzymes preventing their division.
Example: Methotrexate: causes myelosuppression, mucositis. (Check renal and hepatic function).
Folinic acid following methotrexate helps to prevent ADRs.
Example: Capecitabine, which is metabolized to fluorouracil (5FU), for treatment of metastatic colorectal cancer and advanced gastric cancer.

15. Anthracyclines
Antibiotic cytotoxics act as radiomimetics and simultaneous use of radiotherapy should be avoided.
Examples: Daunorubicin, doxorubicin, epirubicin and idarubicin are anthracycline antibiotics.
Treatment of lymphomas and leukaemias
May cause severe cardio toxicity

16. Vinca Alkaloids
Are used to treat a variety of cancers including leukaemias, lymphomas, and some solid tumors (e.g. breast and lung cancer).
Neurotoxicity (reversible), occurs with all vinca alkaloids and is a limiting side-effect of vincristine
Myelosuppression is the dose-limiting side-effect of vinblastine, vindesine, and vinorelbine but not vincristine
The vinca alkaloids may cause extravasation and reversible alopecia.
Examples: Vinblastine, vincristine, vindesine, and vinorelbine injections

17. Hydroxycarbamide Hydroxyurea
Orally active drug used mainly in the treatment of chronic myeloid leukaemia (CML).
Myelosuppression, nausea, and skin reactions are the most common toxic effects.
It is teratogenic.

18. Platinum Compounds
Carboplatin is widely used in the treatment of advanced ovarian cancer and lung cancer.
Oxaliplatin is licensed in combination with fluorouracil and folinic acid, for the treatment of colorectal cancer.
Cisplatin is the most toxic, causing nephrotoxicity, ototoxicity, peripheral neuropathy, and myelosuppression.

19. Protein Kinase Inhibitors
Imatinib, a tyrosine kinase inhibitor, is licensed for the treatment of newly diagnosed CML
Dasatinib, is licensed for the treatment of CML in those who have resistance to or intolerance of imatinib.
Erlotinib, is licensed in combination with gemcitabine for the treatment of metastatic pancreatic cancer.

20. Taxanes
Paclitaxel is considered for inoperable ovarian cancer and in the treatment of metastatic breast cancer
Docetaxel is licensed for use in locally advanced or metastatic breast cancer
Side-effects include hypersensitivity, myelosuppression, peripheral neuropathy, alopecia, persistent fluid retention (commonly with Docetaxel).
Dexamethasone by mouth is recommended for reducing fluid retention and hypersensitivity reactions.

21. Guidelines on handling cytotoxic drugs
1. Trained personnel should reconstitute cytotoxics
2. Reconstitution should be carried out in designated areas
3. Personal protective equipment (PPE) should be used
4. Face and eyes should be protected
5. Adequate care should be taken in the disposal of waste material, including syringes, containers etc..
6. Pregnant staff should not handle cytotoxics
7. Staff dealing with cytotoxics should be monitored

22. Handling of Cytotoxic Drugs
All new chemotherapy agents and supportive care medicines (e.g., antiemetic therapy, analgesics) should be added to health plan formulary.
Pharmacists should determine projected use of investigational agents, clinical pharmacy services that will be needed, and any plans to develop an ambulatory infusion program.
The department must create new policies and procedures to ensure safe handling of chemotherapy agents by all personnel.
These should be conveyed to all personnel through a staff education program, because safe handling of chemotherapy agents can significantly decrease the risk of medication errors and injuries.

23. Many of these agents are carcinogenic, teratogenic, or mutagenic in humans at therapeutic doses.
Danger to health care personnel handling such agents results from both the inherent toxicities of the agents and the extent to which the workers are exposed during drug handling.
The level of contamination that occurs in the work areas used for drug preparation and administration.
Urine mutagenicity or chromosomal damage was thought to be a direct result of cytotoxic exposure.
Other reports correlate these observations of reproductive and birth defect risks in pregnant workers handling cytotoxic drugs.

24. Personal protective equipment (PPE)

25. Adverse Effects of Cytotoxics
Extravasation of intravenous drugs: A number of cytotoxic drugs will cause severe local tissue necrosis if leakage into the extravascular compartment occurs. (anthracyclines cause severe damage)
Vesicant drug: causes blistering, local or extensive tissue necrosis with or without ulceration
Irritant drug: causes burning sensation, pain, tightness, with or without inflammation. No tissue necrosis or ulceration.
These reactions usually are characterized by immediate local burning, itching, and erythema.
Some patients may also experience a “flare” reaction.

26. Alopecia: reversible hair loss is a common complication
Alopecia: reversible hair loss is a common complication. No pharmacological methods of preventing this effect.
Expect hair to begin regenerating 1 to 2 months after therapy is completed. The color and texture of her hair may be altered.
The new hair may be lighter, darker, or curlier as it regrows.
Oral mucositis: A sore mouth is a common complication of cancer chemotherapy (fluorouracil, methotrexate, and the anthracyclines).
Good mouth care (rinsing the mouth and brushing of the teeth with a soft brush) will help.
Topical anesthetics, including viscous lidocaine or dyclonine hydrochloride 0.5 or 1%, often are recommended.

27. Equal portions of kaolin, diphenhydramine, and magnesium or aluminum containing antacids can be used for their anesthetic and astringent properties.
Compounded mouth wash products containing these ingredients as well as antibiotics, nystatin, or corticosteroids.
Corticosteroids provide anti-inflammatory properties, and the antibiotics and antifungals provide antibacterial or antifungal properties.
Another topical agent, sucralfate, may pro-vide some benefit by coating the lesion and reducing discomfort.

28. Tumour lysis syndrome (TLS): occurs as a result of massive cell breakdown following treatment of cancer.
Features include hyperkalaemia, hyperuricaemia, and hyper-phosphataemia with hypocalcaemia.
Renal damage and arrhythmias may follow.
Hyperuricaemia: associated with acute renal failure. Allopurinol should be started 24 hours before treating such tumors and patients should be adequately hydrated.
Reduce mercaptopurine or azathioprine dose if allopurinol needs to be given concomitantly.

29. Nausea and vomiting:
Nausea and vomiting cause distress to many patients and it may lead to refusal of further treatment.
Those affected more often include women, patients under 50 years of age, anxious patients, and those who experience motion sickness.
Symptoms may be:
Acute (occurring within 24 hours of treatment): use 5hydroxytryptamine 5HT3 or serotonin antagonists e.g. Granisetron)
Delayed (first occurring more than 24 hours after treatment). Use Dexamethasone alone or with metoclopramide
Anticipatory (occurring prior to subsequent doses). Use Lorazepam

30. Drugs may be divided according to their emetogenic potential:
Mildly emetogenic treatment— radiotherapy, fluorouracil, vinca alkaloids, and low dose methotrexate.
Moderately emetogenic treatment— taxanes, doxorubicin, and high dose methotrexate.
Highly emetogenic treatment—cisplatin, dacarbazine, and high dose cyclophosphamide.

31. Bone-marrow suppression
All cytotoxic drugs except vincristine and bleomycin cause bonemarrow suppression: neutropenia, thrombocytopenia.
Fever in a neutropenic patient requires immediate broad-spectrum parentral antibacterial therapy.
In selected patients, the duration and the severity of neutropenia can be reduced by the use of recombinant human granulocyte-colony stimulating factors (GCSF).
Symptomatic anaemia is usually treated with red blood cell transfusions or Erythropoetin administered subcutaneously.

32. Reproductive function:
Most cytotoxic drugs are teratogenic and should not be administered during pregnancy, especially during the first trimester.
Regimens with an alkylating drug carry the risk of causing permanent male sterility (there is no effect on potency).
Pretreatment counseling and consideration of sperm banking may be appropriate.
Anthracycline-induced cardiotoxicity:
The anthracycline cytotoxic drugs are associated with dose-related, cumulative, and potentially life-threatening cardiotoxicity.
Dexrazoxane is licensed for the prevention of chronic cumulative cardiotoxicity caused by doxorubicin (cardiomyopathy) or epirubicin treatment

33. Nephrotoxicity
Cisplatin, a heavy-metal complex, is widely used clinically because it has activity against various solid tumors.
The major dose-limiting toxicity of cisplatin is nephrotoxicity, and various renal and electrolyte disorders, both acute and chronic.
Prevented vigourous hydration with saline, mannitol, and prophylactic magnesium.
Other agents include Methotrexate, Ifosfamide.
Haemorrhagic cystitis:
is a common manifestation of urothelial toxicity which occurs with the cyclophosphamide and ifosfamide; it is caused by the metabolite acrolein.
Mesna reacts specifically with this metabolite in the urinary tract, preventing toxicity. Mesna is used routinely in patients receiving these drugs.