Principal of chemotherapy for cancer

1. Cancer and Chemotherapy
- General Principles -
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 If cancer cells are allowed to grow uncontrollably, they can eventually
result in the death of the patient.

2. Chemoprevention
 Chemoprevention focus on reversing carcinogenesis in the early
phases and preventing new malignancies.
 Chemoprevention could include treatment with natural or synthetic
agents that exert its protective effects by:
 Preventing the formation of carcinogens
 Blocking the carcinogen from reacting with critical target sites
 Suppressing the promotion of an epidermal neoplasia (table 86.3).
 If an agent is an effective chemoprotectant, lifelong therapy will
probably be necessary; therefore, ideal chemoprotectants should be
associated with minimal risk and low cost.
 Once-daily dosing( or less) also is desirable to minimize compliance.
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3. Prevention
 Antioxidant vitamins, including β-carotene, vitamin C , and vitamin E
have been purported to reduce the incidence of various malignancies,
including lung, oral, and colon cancers.
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4. Prevention
 Diet:
 Linked to the development of colon, breast, and prostate cancers.
 Colon cancer is third most common cancer in Western world and
colon cancer is rare among African and Japan.
 Diet modification that decrease fat and increase fiber intake could
decrease the risk of colon cancer.
 Incidence of breast cancer is greatest in populations that have
highest fat intake. Life style, alcohol intake too.
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5. Cancer Prevention
 Sun exposure:
 History of sunburn at any time in the
individual’s life increases the risk for
skin cancer.
 1 in 100 Caucasian will develop
melanoma.
 Prevention: limiting sun exposure,
avoid 10am to 2pm
Melanoma
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6. Screening and Early Detection
 Standardized screening tests can help identify disease in asymptomatic
people or help diagnose a disease in symptomatic individuals.
 Screening tests must meet four requirements;
 There must be good evidence that the test is effective in reducing
morbidity or mortality
 the benefits should outweigh the risks.
 It should be cost-beneficial
 It should be practical and feasible
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7. Diagnosis and Staging
 Tumor’s histological diagnosis determines its natural history, pattern
of progression, and responsive to treatment.
 Staging is the process that determines the extent or spread of the
disease and significantly influences its treatment and prognosis.
 Schema have been developed for all major types of cancer, and many
incorporate the TNM system, which incorporates
 The size of primary tumor (T)
 The extent of regional lymph node spread (N).
 The presence of metastatic spread to distant organ (M)
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8.  TNM – most common staging system for solid tumor
 T = tumor, N = node, M = metastases.
 Numerical value is assign to each letter to indicate size or extent
of disease
 Tumor; designated rating describes the size of the primary mass
(T1 to T4). Insitu = Tis
 Nodes: described interms of the extent and quality of nodal
involvement (N0 – N3)
 Metastases: scored depend on presence or absence (M0 or M1)
 Simplify: most cancers are classified according to extent of disease by
a numerical system involving stages I through IV
Diagnosis and Staging
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9. Staging
 Stage I:indicates localized tumor
 Stage II and III: represent local and regional extension of disease.
 Stage IV: denotes presence of distant metastases.
 TNM rating translate into a particular stage classification
 T3N1M0: moderate to large size primary mass, with regional lymph
node involvement and no distant metastases
 For most cancer = Stage III.
 The criteria for classifying disease extent are quite specific for each
type of cancer.
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11. Cancer Treatment Modalities
Four primary modalities are employed
 Surgery
 Radiotherapy
 Chemotherapy (Cytotoxic Drugs)
 Hormonal
 Multimodal
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12. Treatment Principles
 The choice of therapy depends on
-the histology and stage
-on the patient’s predicted tolerance of the side effects and
complication.
 The goal of therapy should always be to cure the patient, and the likely
hood of this is greatest when the tumor burden in low.
 Surgery or radiation is the initial choice of therapy for localized tumors
 Management of most type of cancer involves the use of combined
modalities
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13. Cancer Treatment Modalities
 Surgery & Radiation:
 Play major role in diagnosis and treatment of cancer.
 Treatment of choice for most solid tumor (early stage)
 Radiation: First used 1800 & main stay in cancer. management
 Both effective in ca tx, but are local tx
 Both likely to produce a cure in truly localized disease
 Most ca. pt. have metastatic (m0)disease at diagnosis
 Localized tx often fail to completely eliminate cancer.
 Systemic disease such as leukemia cannot be tx with localized mode.
 Early stage breast ca is a good example of the use of a combined-
modality approach
 Primary tumor is removed surgically
 Radiation tx is delivered to the remaining breast (after
lumpectomy)or to the axilla (if there is marked lymph node involvement).
 Adjuvant chemotherapy and /or hormonal tx is then administered to
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14. Surgery:
 Usually, but not always, the first line of treatment is some form of
surgery.
 Radical surgery involves the complete surgical removal of the
tumour and some surrounding tissue, and the draining lymph
nodes.
 Palliative surgery; conducted when the complete removal of the
tumour may not be possible, only limited surgery is done to relieve
symptoms.
 Following surgery, further treatments are considered
(adjuvant).
.
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15. Radiotherapy:
 Involves the delivery of high energy radiation or X-rays to a specific
part of the body with cancer.
 The normal cells receive a lower dose of gamma radiation
than the cancer cells, where all the rays meet.
 Radiotherapy aims to kill the cancer cells, while doing as
little damage as possible to healthy normal cells.
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16.  Radical radiotherapy; radiotherapy to cure the cancerous tumour,
and is usually of high dose, typically daily for a duration of 6 to 8
weeks.
 Adjuvant radiotherapy; radiation is given as an adjunct after the
main treatment, usually surgery, to sterilize possible microscopic
residual disease in the tumour bed.
 Palliative radiotherapy; radiation treatment delivered just to relieve
the symptoms of advanced and incurable cancer.
 The actual treatment takes only a few minutes but the whole session
can last 15 to 30 minutes due to the time required to set up the
equipment and position the patient.
Radiotherapy:
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18. Radiotherapy: Side Effects
 Depend on the part of the body receiving the radiation, the
radiation dose and the size of the treatment fields.
 The effects usually manifest after a few weeks of starting the
radiation treatment.
 Some side effects may only be seen many years later.
 Most are temporary and reversible after treatment although some
side effects may be permanent.
A. Temporary
lethargy and fatigue, Skin redness, loss of hair in treated
area,Sore throat, mouth ulcers, difficulty in swallowing,Nausea,
Diarrhea, Loss of appetite,Frequency of passing urine.
B. Permanent
Dryness of mouth due to poor salivary function,Menopause,
Sterility,Nerve damage (rare).
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19. Chemotherapy; - Cytotoxic Drugs
Highly Hazardous !!!
- Should be handled with care
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20. Clinical Pharmacology of Anticancer Agent
 Antimetabolites:
 Fluorouracil, Capecitabine,
 Cytarabine, Gemcitabine,
 Mercaptopurine and Thioguanine,
 Methotrexate
 Microtubule-targeting drugs:
 Vincristine, Vinblastine and Vinorelbine,
 Paclitaxel and Docetaxel
 Topoisomerase-targeting drugs:
 Etoposide and Teniposide,
 Irinotecan and Topotican,
 Anthracene: Doxorubicin, Daunorubicin, Idarubicin and
Epirubicin
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21. Clinical Pharmacology of Anticancer Agent
 Alkylating agents:
 Cyclophosphamide and Ifosfamide,
 Nitrosureas: BCNU and CCNU
 Nonclassic AA: Dacarbazine
 Heavy metal compounds
 Cisplatin and Carboplatin
 Misellaneous agents
 Bleomycin,
 Hydroxyurea, Asparaginase,
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22. Chemotherapy
 Cytotoxic chemotherapy kills cancer cells by damaging DNA or
interfering with DNA synthesis or other steps during cell division.
 They are most cytotoxic to tumor cells with a high–growth fraction.
 Phase-specific or schedule-dependent agents affects the cell only
during a specific phase of the cell cycle.
 Phase-nonspecific or dose-dependent agents affect the cell during
any phase of the cell cycle.
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 Curative
 Palliative
 Primary
 Adjuvant
 Neoadjuvant

23. Cancer Treatment Modalities
 Adjuvant therapy
 given at the time that the cancer is undetectable,
 its effectiveness cannot be measured by response rates;
 instead it is evaluated by recurrence rates and survival
 The value of adjuvant tx is best established in colorectal and
breast ca.
 Neoadjuvant Ctx (preoperative).
 Goal is to make other tx modalities more effective by reducing
tumor burden and to destroy -metastases
 Eg: head and neck cancer,
 neoadjuvant ctx is employed in an attempt to shrink large tu
 make them more amendable to later surgical resection
 and possibly spare critical organs sa larynx
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24. Breast Cancer CTx Protocol-EXAMPLE
CMF Regimen
 Cyclophosphamide
 Methotrexate
 5-Fluorouracil
Repeat day 22 x 6 cycles
600 –750 mg/m2 IV day 1
40 –50 mg/m2 IV day 1
600 mg/m2 IV day 1
FAC (CAF) Regimen
 5-Fluorouracil
 Doxorubicin
 Cyclophosphamide
Repeat day 22 x 6 cycles
600 mg/m2 IV day 1
30 – 50 mg/m2 IV day 1
600 mg/m2 IV day 1
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25. Tumor that Respond to Chemotherapy
 Advanced tumors that can be cured with chemotherapy
 Choriocarcinoma, ALL, testicular, AML, NHL, neuroblastoma,
SCLC
 Chemotherapy used as adjuvant therapy with curative intent
 Breast, Colorectal, Ovarian, Wilm’s, Ewing’s sarcoma
 Chemotherapy used as neoadjuvant therapy with potential curative
intent
 Head and neck, cervical, osteosarcoma
 Advanced tumors in which chemotherapy may prolong survival or
palliate symptoms
 Multiple myeloma, pancreatic, bladder
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26. Chemotherapy and Cell Cycle
 Cell Cycle
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27. Response Criteria
 Response to chemotherapy may be described as
1. 1. Cure 2. complete response 3.partial response 4.stable
disease or progression.
1. Cure:
 Patient is entirely free of disease
 Same life expectancy as a cancer-free individual
 No way to absolutely certain that an individual patient is cured.
 Stable plateau in the survival curve after cancer treatment is taken as
evidence of cure.
 5 years of survival wo diseased recurrence is equated with cure
 Some malignancies, pt still at risk for relapse after 5 years
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28. Response Criteria
 Complete Response (CR).
 Complete disappearance of all cancer wo evidence of new disease
for at least 1 month after treatment .
 “Cure” and “CR” are not synonymous.
 Must have a CR to be cured, many who achieve CR will eventually
relapse
 Partial Response (PR).
 50% / > decrease in the size or other objective disease marker
 No evidence of any new disease for at least 1 month
 Overall Response Rate = CR + PR
 Despite small changes in tumor size, some pt may experience
subjective improvement in the symptoms .
 Clinically important, but does not indicate an objective response 28

29. Cancer Survival Curve
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30. Response Criteria
 Clinical Benefit Response,
 Refer to pt who have clinical benefit as measured by decreased in
pain or analgesic consumption,
 or improved quality of life or performance status.
 Stable Disease
 Tumor size neither grow nor shrinks by >25%.
 Progression of disease
 25% increase in tu size or development of new lesions while
receiving tx.
 Above response definition
 applicable to solid tumor.
 Leukemia and multiple myeloma are not characterized by discrete,
measurable masses.
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31. Assessing Response to therapy
 Tumor markers;
 - are biochemical indicators commonly found in abnormally high
concentration with cancer.
 They should be produced and released primarily by the cancer
cells at level proportional to the tumor mass and should be
detectable at low levels
 Table 86.17 – Tumor markers.
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33. Factors Influencing Response
to Chemotherapy
 Dose intensity:
 Schedule dependency.
 Drug resistance.
 Tumor site:
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34. Factors Influencing Response
to Chemotherapy
 Dose intensity:
 Equals the amount of chemotherapy administered per unit of time.
 Unnecessary lengthening of interval between successive course
of chemotherapy or decreasing the dose can negatively effect
treatment outcome.
 Eg. Reducing a dose can cause treatment failure in patients with
chemo-sensitive tumors who are undergoing their first chemo tx.
 There is a direct relationship between dose intensity and response
rate, but this is limited by toxicity.
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35. Factors Influencing Response
to Chemotherapy
 Schedule dependency.
 The schedule of chemotherapy administration can reduce toxicity
and allow greater dose intensity.
 Eg. Changing administration schedule can reduce the toxicity enough
to allow patients to receive higher total doses or more frequent
courses of therapy to increase the dose intensity.
 Rate of administration are also determined by the pharmacokinetic
properties of an agent
 Eg. If agent with a short half-life is administered by IV bolus, a
significant number of tumor cells will probably not cycle through the
vulnerable phase of the cell cycle during exposure to this agent.
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36. Factors Influencing Response
to Chemotherapy
 Drug resistance.
 Biochemical resistance to chemotherapy is a major impediment to
successful treatment. It can develop during cell division by several
mechanisms (mutation).
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37. Factors Influencing Response
to Chemotherapy
 Tumor site:
 The cytotoxic effects of chemotherapy agents are related to the
time the tumor is exposed to an effective concentration (C x T).
 This is determined by the dose, route, and lipophilicity of the drug,
as well as tumor size and location.
 Eg. As tumors grow larger, their degree of vascularity lessens,
making it more difficult for agents to penetrate the entire tumor
mass.
 Tumors located in sites of the body with poor drug penetration
(brain) may not receive a sufficient concentration to provide
effective kill
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38. Combination Chemotherapy
 Objective:
 To provide broader coverage against resistant cell lines within a
heterogenous tumor.
 Because most tumors show only a partial response of a very short
duration to single-agent therapy.
 Agents used together:
 Should have activity against the tumor as a single agent
 Should have different mechanism of actions
 Should not have overlapping toxicities
 Should be used in their optimal dose and schedule
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39. Cytotoxic Drug: Dosage
1. Body surface Area (BSA /m2) eg. CPM 750mg/m2
1. Calculation /Nomogram
2.
3.
4.
5.
6.
7.
Body weight ( infant)
Age: Intrathecal : 6m, 1 y, 1 ½ y, 2 y, 2 ½ y, 3 y = adult
AUC: Carboplatin
Flat dose : eg. bleomycin 15mg
Total cumulative dose: Anthracycline: Doxorubicin 550mg/m2
Maximum dose:
1.
2.
Vincristine= 1.4mg/m2 = 2mg
Vinblastine= 6 mg/m2 = 10mg
8. Test dose
1. Asparaginase , Bleomycin
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40. Administration
 Systemic chemotherapy;
 Commonly administered as;
 IV bolus (<15 minutes),
 short infusion (15 minutes to several hours),
 continuous infusion (24 hours to several weeks).
 Some can be administered orally.
 Regional chemotherapy is that administered locally to specific sites of
the body affected by the tumor.
 Allows high concentrations of agents to be achieved at the site of
the tumor while reducing systemic exposure and subsequent
toxicity.
 Disadvantage: undetectable metastases at distant site may not be
exposed to chemotherapy
 Table 86.15 – Regional Routes
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41. Route of Administration
1. IV slow bolus; 3 – 5 min
2. IV Infusion: intermittent /continuous
3. IM max = 2ml , SQ max = 1ml, N. saline, no alcohol
4. Intrathecal; N.Saline, adult = 5ml, Pead = 2ml, 3 in 1
5. Intraventrical: N.saline, adult = 2ml, Pead = 2ml, 3 in 1
6. Intravesical: Mitomycin C, Water for injection, bladder installation
7. Intrapleural: Mustine, pleural effusion, pleural installation
8. Intraperitoneal: Cisplatin, Ca Ovary, 3 L N Saline, body temp
9. Intraarterial: Doxorubicin: ca liver
10. Oral: MTX, 6MP, 6TG, ALL pead
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43. Administration procedures
 Per hospital procedures
 MO, Oncology Nurse, Nurse
 Verify each dose
 Bolus / Infusion
 PPE
 Premedications
 Hydration
 Vesicant first
 Avoid weekend / public holidays
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44. Compatibility and Stability
 Diluents
 Water for injection, Bacteriostatic water
 Saline, Bacteriostatic saline
 Infusion fluid
 Dextrose
 Saline.
 Final concentration: VP16
 Final volume: IT, IM, SQ
 Infusion container: Paclitaxel
 Infusion set
 Temperature: IP, Cisplatin
 Storage: RT or Refrigerator
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45. Premedication & Antiemetics
 Paclitaxel: hypersentivity reaction
 Dexamethasone
 H1 antagonist
 H2 antagonist.
 Antiemetic:
 Dexamethasone
 Metoclorpramide
 5HT3 blocker.
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46. Hydration – Nephrotoxic drugs
 Cisplatin
 Dextrose/ Saline
 + Mannitol + KCl + MgSo4
 Cyclophosphamide: haemorrhagic cystitis
 Ifosfamide: haemorrhagic cystitis
 + Mesna
 Methotrexate
 Dextrose / Saline
 + KCl + Na Bicarb.
 .
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47. Rescue drugs – High Dose MTX
 Methotrexate High Dose
 Folinic acid, .
 Need to take MTX level,
 Therapeutic Drug Monitoring (TDM) Service
 No TDM service = No High Dose MTX.
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48. Intrathecal Administration
 Methotrexate
 Cytarabine
 Hydrocortisone
 Dose = /age
 3 in 1
 Final Volume
 Peadiatric: 2ml
 Adult. 5 ml
 Preservative free
 No vesicant drugs.
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49. Vesicant and Extravasation
 Vinca alkaloid
 Vincristine
 Vinblastine
 Vinorelbine
 Antracycline
 Doxorubicin
 Daunorubicin
 Epirubicin
 Idarubicin
 .
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