basic principles of chemotherapy including the treatment aim by definitions. Types and classes of chemotherapeutic agents and drug combination idea and its side effects .how to proceed prior to administration

1. Your way in chemotherapy
administration
Dr” Mona Quenawy
Lecturer of clinical oncology
Ain Shams university

3. Outline:
 chemotherapy by definition
 Indications of chemotherapy
 Adjuvant treatment
 Neoadjuvant chemotherapy
 Pretreatment
 Dose calculation
 Dose capping
 Before administration
 Chemotherapy classes

4. Cytotoxic chemotherapy: mode of action
• Cytotoxic chemotherapy drugs are systemic therapies that aim to kill or slow the growth of tumor cells while being
relatively sparing to normal cells.
• The sensitivity of different tumor types to the actions of chemotherapy drugs varies widely among the cells of origin and
across the range of drugs. In curable cancers, malignant cells can be many times more sensitive to cytotoxic drugs than the
cells they have arisen from and, fortunately, more sensitive than the cells of the bone marrow. In the more common
malignancies
• ,
Definitions and basic
principles

5. tumor cells are generally more sensitive to cytotoxic drugs than are their parent cells, but they are insufficiently
sensitive to achieve a cure
.
Alongside this major divide between the differing types of malignancy, there is a wide range of activity of the different
chemotherapy drugs across the different tumors.
Whereas the majority of chemotherapy drugs have been developed empirically, the mechanisms for the greater
effectiveness of some drugs in some tumours
Cytotoxic chemotherapy: mode of action:cont Definitions and basic
principles

6. There are three main indications for the use of chemo- therapy:
Curative
 The management of patients with curable advanced malignancies including choriocarcinoma, testicular cancer,
Hodgkin lymphoma and high-grade non- Hodgkin lymphoma(NHL).
Improve survival
 The preoperative or postoperative adjuvant treatment of localized malignancies, primarily breast cancer and
colorectal cancer.
 Palliation
 The treatment of patients with advanced incurable malignancies, where the primary aim i s palliation and symptom
control,
Aims of chemotherapy treatment Definitions and basic
principles

7. 1-Adjuvant chemotherapy
Adjuvant Chemotherapy
Adjuvant therapy refers to the
use of chemotherapy or
radiation in addition to surgery,
Definitions and basic
principles

8. Neoadjuvant therapy
Refers to the use of chemotherapeutic agents or radiation therapy
before surgery in patients with advanced but locally confined
malignancy.
Aims
Improve pathological response
Prolong survival
To downsize the tumor making it more resect able
Definitions and basic
principles

9. Definitions and basic
principles

10. • Historically, the mode of action of many chemotherapy drugs has been divided
between those termed‘
• cell-cycle specific’
• The cycle-specific drugs, such as the antimetabolites
(methotrexate, fluorouracil and gemcitabine), interact predominantly with cells that
are actively synthesizing new DNA in the S phase.
• These drugs are most effective in tumors with high mitotic indices, and they
produce greater cell kill if given in prolonged exposures, killing larger number s a s
cells move through to the S phase. In contrast
• cell-cycle non-specific.’
• the cell-cycle non-specific drugs interact with cells in all parts of the cycle and they
can be cytotoxic to more slowly proliferating tumor cells. The common cell-cycle non-
specific drugs such as the alkylating agent s and the antitumor antibiotics have
activity at all phases of the cell cycle, and cell killing is more closely linked to the total
dose rather than to the duration of administration.
•
Cell-cycle specificity Definitions and basic
principles

11. Chemotherapy combination
chemotherapy drugs are generally combined with others into combination chemotherapy schedules.
Single-agent therapy does remain a part of palliative chemotherapy for several tumor types; however, the best
results from chemotherapy are usually with a combination of drugs,

12. The principles of choosing combinations of chemotherapy
are as follow:
Each drug is active against the tumor as a single agent.
There are no clinically important drug interactions between the agents.
Combinations should avoid drugs of the same class or those with similar modes of action.
The drug

13. Scheduling and administration of chemotherapy
The most frequent situation where this applies is the combination of paclitaxel and carboplatin in the
treatment of patients with ovarian cancer.
Carboplatin is a cell-cycle non-specific drug; thus, it would be suited to bolus administration in a single
large dose. However, because of the risk of hypersensitivity, it is given as an infusion over a minimum of 30
minutes rather than as a bolus. It is also potentially unstable, especially in poly(vinyl choride) (PVC)
containers, and so the final volume of the infusion is also critical. The myelosuppression nadir from
carboplatin is between 14 and 21 days, which would indicate administration using a 28- day cycle.

14. Routine cytotoxic chemotherapy doses continue to be calculated according to the
patient’s body surface area (BSA)
Calculation of doses
Body surface area

15. Using the calculated BSA in large and obese patients may lead to relative overdosing of chemotherapy with an associated
risk of excess toxicity.
To place an upper limit on drug dose, dose capping is frequently used, and many institutions will use 2.2 m2 as an upper
limit for curative and adjuvant treatment sand 2m2 for palliative treatments.
However, care should be taken when prescribing for tall, non-obese individuals because there is a potential risk of
underdoing if the BSA is capped at 2.2m2. An exception to the 2.2 m2 cap is with the use of vincristine; with this drug,
the dose is usually capped at2mg,soalthoughthedoseis1.4mg/m2 in the CHOP regimen, all but the smallest patients
receive a capped dose of2mg.
Dose capping

16. SPECIAL CASE
Among the commonly used chemotherapy drugs, carboplatin is the only one to have its dose calculated directly
according to the renal function. This drug is excreted unchanged by the kidneys, and a formula has been
developed (the Calvert equation) which is based on renal function(Calvertetal.,1989).The desired AUC (area
under the curve of serum levels against time) is chosen, and the dose is calculated by the following formula:
Dose(mg)=desired AUC×(GFRml/min+25)
Area under the curve (AUC) dosage

17. Pretreatment investigations and checks Before initiating
Informed consent
Disclosure of the patient's diagnosis, the nature of the proposed intervention, intended benefits, associated risks
and side effects, and medically reasonable alternatives (and their corresponding risks and side effects).
Cardio toxic drugs
Echocardiography and clinical examination for certain types like anthracycline
Lab investigations
Complete blood count
Renal function
Hepatic function

18. Alkylating Agents
Examples of alkylating agents are as follows:
•Nitrogen mustard- bendamustine, cyclophosphamide, ifosfamide
•Nitrosoureas – carmustine, lomustine
•Platinum analogs – carboplatin, cisplatin, oxaliplatin
•Triazenes- Dacarbazine, procarbazine, temozolamide
•Alkyl sulfonate- Busulfan
•Ethyleneimine- Thiotepa
Mechanism of action (MOA): These drugs yield an unstable alkyl group, R-CH2+, reacting with
nucleophilic centers on proteins and nucleic acids. Inhibit DNA replication and transcription.
Toxicity: Dose-limiting toxicity: myelosuppression (neutropenia nadir: 6 to 10 days with recovery in 14 to
21 days). Mucositis, nausea and vomiting, neurotoxicity, alopeciaLong-term toxicities: pulmonary fibrosis,
infertility, secondary malignancies

19. Antimetabolites
Mechanism of Action: Inhibit the replication of DNA
Examples of antimetabolites are as follows
A) Cytidine analogs – azacitidine, decitabine, cytarabine, gemcitabine
•MOA: Directly incorporate into DNA and inhibit DNA methyltransferase
(azacitidine, decitabine) or DNA polymerase (cytarabine, gemcitabine)
•Indications: Azacitidine and decitabine for MDS, AML, cytarabine for MDS,
AML, and gemcitabine for breast, NSCLC, ovarian, pancreatic, bladder, sarcoma,
HL, NHL
•Toxicity: Myelosuppression in general. Cytarabine high dose causes
neurotoxicity, conjunctivitis. Gemcitabine causes liver enzyme elevations,
interstitial pneumonitis.

20. Folate antagonists – methotrexate, pemetrexed
•Work to reduce folate, which is essential in the synthesis of purine nucleotides and
thymidylate
•Indications: Methotrexate for ALL, NHL, CNS, sarcoma, and pemetrexed for malignant
pleural mesothelioma, NSCLC (non-squamous)
•Toxicity: Myelosuppression, mucositis, hepatotoxicity, nephrotoxicity, cutaneous
reactions
•Toxicity prevention: Hydration and alkalization of the urine, leucovorin rescue

21. Purine analogs – cladribine, clofarabine, nelarabine
•structural analogs of guanine and act as false metabolites
•Indications: Cladribine for hairy cell leukemia, AML, CLL, NHL. Clofarabine for ALL,
AML. fludarabine for CLL, AML, NHL, BMT conditioning agent. Nelarabine for T-
ALL, lymphoma. Pentostatin for hairy cell leukemia, CTCL, CLL.
•Toxicities: Myelosuppression, immunosuppression (suppress CD4+ cells) put patients
at risk for opportunistic infections

22. Pyrimidine analogs – fluorouracil (5-FU), capecitabine (prodrug of 5-FU).
•Active metabolite (F-dUMP) forms a stable covalent complex with thymidine synthetase
in the presence of reduced folate, therefore, interfering with DNA synthesis and repair.
•Indications: 5-FU for colorectal cancer, anal cancer, pancreatic cancer, gastric cancer.
Capecitabine for colorectal cancer, breast cancer.
•Toxicity: Dose-limiting hand-foot, mucositis, diarrhea. Dose-limiting
myelosuppression.[14] Toxic levels of 5FU can occur in patients with Dihydropyrimidine
Dehydrogenase (DPD) deficiency or drug overdose. This can lead to cardiac dysfunction,
colitis, neutropenia, and encephalopathy. Uridine triacetate is approved for the toxicity of
these patients

23. •Antimicrotubular Agents
Examples of antimicrotubular agents are as follows:
A) Topoisomerase II inhibitors: Anthracyclines [doxorubicin, daunorubicin, idarubicin, mitoxantrone inhibit
RNA and DNA synthesis. In addition, it inhibits topoisomerase II, causing inhibition of DNA repair resulting
in blockade of DNA and RNA synthesis.
•Indications: Daunorubicin for ALL, AML, APL. Doxorubicin is used for ALL, AML, Wilms tumor,
neuroblastoma, sarcomas, breast, ovarian, bladder, thyroid, HL, and NHL. Liposomal doxorubicin has a longer
half-life and is less cardiotoxic.
•Toxicity: Myelosuppression, cardiotoxicity (cumulative), mucositis. The lifetime cumulative dose of
Adriamycin is 550 mg/m^2.
•Secondary malignancies like treatment-related MDS/AML(t-MDS/t-AML) is a rare complication with poor
prognosis have been reported often from alkylating agents and topoisomerase II inhibitors

24. Topoisomerase I inhibitors: Irinotecan, Topotecan
• prevents relegation by blocking the release of Top I from the cleavable complex & forming
a ternary complex
•Indications: Irinotecan for colorectal, cervical, esophageal, sarcoma, pancreatic, lung.
topotecan for cervical, ovarian, SCLC
•Toxicity: Irinotecan causes dose-limiting diarrhea. Topotecan causes dose-limiting
neutropenia, thrombocytopenia.

25. Vinca alkaloids: vinblastine, vincristine, vinorelbine
• Bind to tubulin and inhibit microtubule formation arrests cell in metaphase. M-phase
specific.
•Indication: Vincristine for ALL, HL, NHL, Neuroblastoma, SCLC
•Toxicity: Peripheral neuropathy (both motor and sensory function affected),
myelosuppression

26. Taxanes – paclitaxel, docetaxel, cabazitaxel
•Works by Disruption in the equilibrium of polymerization and depolymerization of
microtubules causing abnormal cellular function and disruption of replication leading to
apoptosis. Inhibit assembly of microtubules—M phase-specific.
•Indications: Docetaxel for breast, lung, prostate, ovarian, cervical, sarcoma. paclitaxel for
breast, lung, and ovarian. Abraxane is protein bound paclitaxel. Cabazitaxel for prostate
cancer.
•Toxicity: Hypersensitivity reactions, myelosuppression, peripheral neuropathy

27. •Antitumor Antibiotics
• Inhibit RNA and DNA synthesis
•Bleomycin binds to DNA, producing single and double-strand DNA breaks.
Examples of antibiotics used as chemotherapy agents are as follows: actinomycin D,
bleomycin, daunomycin:
•Indications: Testicular, HL, Head, and neck cancers
•Toxicity: Cumulative pulmonary toxicity, hyperpigmentation