Chemotherapy is the main treatment for disseminated cancers. It involves using multiple drugs in cycles to target rapidly dividing cancer cells. Common drugs include alkylating agents, antimetabolites, microtubule inhibitors, and monoclonal antibodies. Combination chemotherapy aims to maximize responses while avoiding overlapping toxicities. Doses are based on body surface area and adjusted for individual factors. Treatment intervals allow time for normal tissues to recover between cycles. Toxicities include myelosuppression, nausea/vomiting, and alopecia. Response is evaluated based on tumor shrinkage or progression.

1. CHEMOTHERAPY IN
CANCER
MODERATOR DR SHEHTAJ KHAN
COMODERATOR PROF S A SIDDIQUI
PRESENTED BY : DR.YASHVEER SINGH
DATED 07/09/2015

2. CHEMOTHERAPY
• Systemic chemotherapy is the main treatment available for
disseminated malignant diseases.
• Progress in chemotherapy resulted in cure for several
tumors.
• Chemotherapy usually require multiple cycles.

3. Paul Ehrlich 1854 - 1915
• Father of Chemotherapy
• Nobel Prize 1908

4. HISTORICAL PERSPECTIVE
• Nitrogen mustards were a product of the secret war gas
programs in both world wars
• In WWII, an explosion at Bar Harbor exposed seamen
to mustard gas - they developed severe marrow and
lymphoid hypoplasia
• Led to the use of these agents to treat Hodgkins and
non-Hodgkins lymphomas at Yale in 1943

5. 1965, The era of combination chemotherapy begins.
# POMP(Methotrexate,Vincristine,6MP,Prednisolone) regimen was
able to induce long term remission in children with
ALL
# MOPP(Nitrogen Mustard,Vincristine,Procarbazine,Prednisolone)
regimen successfully cured HL and NHL used by
Vincent DeVita and collegues in 1970
Currently, nearly all successful cancer chemotherapy
regimens use this paradigm of multiple drugs given
simultaneously, called combination chemotherapy or
polychemotherapy.

6. The concept adjuvent Chemotherapy came out in 1972
when Emil Frei and collegues demonstrated
chemotherapy given after surgical removal of
osteosarcoma improves the cure rate.
In 1992 FDA approved Paclitaxal which become the
blockbuster of Oncology drugs in present scenario
2004, FDA approved Bevacizumab, the first clinically
proven antiangiogenic agent for colon cancer.

7. ANTICANCER DRUGS

8. • Cell Cycle Specific Drugs:
• Antimetabolites
• Bleomycin peptide antibiotics
• Vinca alkaloids
• Cell Cycle non-Specific Drugs:
• Alkylating agents
• Antibiotics (Dactinomycin)
• Cisplatin
Chemotherapeutic Agents
Effective for high
growth-fraction-
malignancies,
such as
hematologic
cancers.
Effective for
both low-growth
(solid tumors)
and high growth
fraction
malignancies

9. 1. Alkylating agents:
• Major interaction: Alkylation of DNA
• Binds to nucleophilic groups on various cell
constituents. Including DNA
• Primary DNA alkylation site: N7 position of
guanine (other sites as well)
• Major Toxicity: bone marrow suppression
Chemotherapeutic Agents
Cyclophosphamaide
Carboplatin
Cisplatin
Oxaliplatin
Dacarbazine

10. Chemotherapeutic Agents
2. Antimetabolites:
•Structurally related to normal compounds that exist
within the cell.
•Interfere with the availability of normal purine or
pyrimidine nucleotide precursors, either by inhibiting
their synthesis or by competing with them in DNA or
RNA synthesis.
•Their maximal cytotoxic effects are in S-phase and
therefore are cell-cycle specific.
5-FluoroUracil
Gemcitabine
Cyterabine
Methotrexate

11. 3. Microtubule Inhibitors:
• These are plant-derived substances .
• Cause cytotoxicity by affecting the equilibrium
between the polymerized and depolymerized
forms of the microtubules.
• Vinca alkaloids inhibit microtubule
polymerization and increase microtubule
disassembly. The mitotic spindle apparatus is
disrupted, and segregation of chromosomes in
metaphase is arrested.
Chemotherapeutic Agents
Vinca Alkaloids
Vincristine
Vinblastine
Vinorelbine
Taxanes
Paclitaxel
Docetaxel

12. 4. Antineoplastic Antibiotics:
• Interacts with DNA, leading to disruption of DNA
function.
• Also Inhibit topoisomerases (I and II) and
produce free radicals.
• Cell-cycle nonspecific.
• Eg: Actinomycin D binds with double-stranded
DNA and blocks the action of RNA polymerase,
which prevents DNA transcription.
Chemotherapeutic Agents
Bleomycin
Doxorubicin
Dactinomycin
Daunorubicin

13. 5. Hormonal Agents:
• Commonly involves the use of glucocorticoids.
• Direct antitumor effects are related to their
lympholytic properties;.
• Glucocorticoids can inhibit mitosis, RNA synthesis,
and protein synthesis in sensitive lymphocytes.
• Considered cell-cycle nonspecific .
• Resistance to a given glucocorticoid may develop
rapidly and typically extends to other
glucocorticoids.
Chemotherapeutic Agents
Prednisone
Tamoxifen
Estrogens
Flutamide
Nilutamide
Bicalutamide

14. • Antibodies that are made in the lab rather than
by a person's own immune system.
• Directed at specific targets and often have
fewer adverse effects.
• Designed to recognise and find specific
abnormal proteins on cancer cells.
• Each monoclonal antibody recognizes one
particular protein.
Chemotherapeutic Agents
Rituximab
Trastuzumab
Cetuximab
Bevacizumab
6. Monoclonal Antibodies:

15. ETIOLOGY OF
CANCER• Carcinogenesis
– A cancer, is thought to develop from a cell in which the
normal mechanisms for control of growth and
proliferation are altered.
– Current evidence supports the concept of carcinogenesis
as a multistage process that is genetically regulated

16. ETIOLOGY OF
CANCERGenetic and Molecular Basis of Cancer
• Two major classes of genes are involved in carcinogenesis:
oncogenes and tumor suppressor genes

18. GOMPERTZIAN GROWTH
• Growth rates are exponential at early stages of development
and slower at later stages of development
Biological growth follows this characteristic curve.Biological growth follows this characteristic curve.

19. GOMPERTZIAN GROWTH MODEL
Initial tumour growth is first order, with later growth being
much slower
Smaller tumour grows slowly but large % of cell dividing
Medium size tumour grows more quickly but with smaller
growth fraction
Large tumour has small growth rate and growth fraction

20. Log kill hypothesis
• According to the log-kill hypothesis, chemotherapeutic
agents kill a constant fraction of cells (first order kinetics),
rather than a specific number of cells, after each dose
1. Solid cancer tumors - generally have a low growth
fraction thus respond poorly to chemotherapy & in most
cases need to be removed by surgery
2. Disseminated cancers- generally have a high growth
fraction & generally respond well to chemotherapy

21. Log kill hypothesis:

22. Clinical Implications of Fractional Cell Kill

23. Pre chemo asssesment
• HISTORY
• EXAMINATION
• ROUTINE INVESTIGATIONS
CBC
RFT BS SE
LFT
ECG
URINE (R/M)

24. GOALS
Goals of treatment must be clearly defined
1.cure vs. palliation
2.acceptable toxicity
3.quality of life

25. MODES OF CHEMOTHERAPY
• PRIMARY CHEMOTHERAPY - chemotherapy is used as the sole
anti-cancer treatment in a highly sensitive tumor types
– Example – CHOP for Non-Hodgkins lymphoma
• ADJUVANT CHEMOTHERAPY – treatment is given after surgery
to “mop up” microscopic residual disease
– Example – Adriamycin, cyclophosphamide for breast cancer
• NEOADJUVANT CHEMOTHERAPY – treatment is given before
surgery to shrink tumor and increase chance of successful resection
– Example – Adriamycin, ifosfamide for osteosarcoma

26. MODES OF CHEMOTHERAPY
CONCURRENT CHEMOTHERAPY
Treatment is given simultaneous to radiation to increase
sensitivity of cancer cells to radiation
– Example – Cisplatin, 5-fluourouracil, XRT for head and
neck tumors
PALLIATIVE OR CURATIVE
CHEMOTHERAPY
– metastatic cancers

27. Routes of administration
of chemotherapy
Intrathecal, intraventricular in meningeal
metastases from leukemia, lymphoma, breast
cancer etc.
Intrapericardial — in malignant pericardial
effusions
Intraperitoneal in ovarian cancer, colorectal cancer,
mesothelioma.
Intra-arterial in liver cancer
Isolated limb perfusion in melanoma
Intravenous most common route
Oral

28. Repeated intravenous
administration may lead to
peripheral thrombo-phlebitis
and venous inaccessibility. In
order to avoid repeated venu‑
puncture, increased access
and permit patient mobility
particularly in continuous
infusion regimes, Port-a-cath
was developed for
implantation under the skin
and central venous access

29. There is a wide variation in sensitivity of
various cancers to chemotherapy
HighHigh IntermediateIntermediate LowLow
LymphomaLymphoma BreastBreast Head and neckHead and neck
LeukemiaLeukemia ColonColon ProstateProstate
Small Cell Lung cancerSmall Cell Lung cancer Non-small cell lungNon-small cell lung
cancercancer
GastricGastric
Testicular cancerTesticular cancer PancreaticPancreatic

30. CANCER CHEMOTHERAPY:
PRINCIPLES
1. Conventional chemotherapy targets have
been the cell cycle, microtubules and
DNA.
2. Combination chemotherapy improves
responses over single agent, but dose
intensity must be maintained.

31. PRINCIPLES FOR COMBINATION
CHEMOTHERAPEUTIC REGIMENS
• Rationale:
– minimize resistanceminimize resistance
– maximize synergy/additivitymaximize synergy/additivity
– avoid drugs of overlapping toxicityavoid drugs of overlapping toxicity
– biochemical considerationsbiochemical considerations

32. • Rationale:
–biochemical considerations:
• addition of an agent to overcome drug resistance (eg
MDR inhibitor & vinca alkaloid)
• cooperative inhibition (eg leucovorin & 5FU)
• inhibition of drug breakdown (eg DPD inhibitor & 5FU)
• rescue host from toxic effects of drug (eg leucovorin
following high-dose methotrexate)

33. CANCER CHEMOTHERAPY:
PRINCIPLES
More is better, to a point!
A
B
V
D
FFP: 81%
M
O
P
P/
A
B
V
FFP: 67%
A
B
V
D
FFP: 65%
M
O
P
P
FFP: 63%
S
I
N
G
L
E
A
G
E
N
T
FFP: 20%
Advanced Hodgkin’s Disease

34. Careful Sequencing is Critical
Docetaxel Doxorubicin
Doc Dox
40 mg/m2 50 mg/m2
Dox Doc
50 mg/m2 70 mg/m2
Itoh et al. Study of Sequence Switching of Administration
Clin. Cancer Res 6:4082-4090, 2000

35. PLANNING DRUG DOSES AND
SCHEDULES
• Doses
- based on body surface area
- differ between children and adults
- adjusted for people who are elderly, have poor
nutritional status, have already taken or taking
other medications, have already received or are currently
receiving radiation therapy, have low blood cell counts, or
have liver or kidney diseases

36. PLANNING DRUG DOSES AND
SCHEDULES
• Schedule (Cycles)
- A cycle = one dose followed by several days or weeks
without treatment for normal tissues to recover from the
drug’s side effects
The number of cycles = based on the type and stage of
cancer, and side effects

37. HEMATOLOGICAL
CONSIDERATIONS FOR DOSE
SCHEDULING
• Lifespan
– Platelet - 7-10 days
– Red blood cell - 120 days
– Neutrophils - 6-12 hours
• Time from Stem Cell to Mature Neutrophil
– ~7-10 days

38. DECIDING ON TREATMENT
INTERVALS
• As short as possible
• Recovery of bone marrow
– Supplies mature cells for 8-10 days
– Onset 9-10th days
– Lowest (nadir) 14-18th
days
– Recovery by day 21-28.
• Usual schedule is q21-28 days.

39. COMPLICATION OF
CHEMOTHERAPY
• Every chemotherapeutic will have some
deleterious side effect on normal tissue .
• E.G; Myelosuppression,nausea&vomiting,
Stomatitis,and alopecia are the most frequently
observed side effects.

40. SIDE EFFECTS OF
CHEMOTHERAPY
Mucositis
Nausea/vomiting
Diarrhea
Cystitis
Sterility
Myalgia
Neuropathy
Alopecia
Pulmonary fibrosis
Cardiotoxicity
Local reaction
Renal failure
Myelosuppression
Phlebitis

41. Distinctive Toxicities of Some Anticancer Drugs
Toxicity Drug(s)
Renal Cisplatin,* methotrexate
Hepatic 6-MP, busulfan, cyclophosphamide
Pulmonary Bleomycin,* busulfan, procarbazine
Cardiac Doxorubicin, daunorubicin
Neurologic Vincristine,* cisplatin, paclitaxel
Immunosuppressive Cyclophosphamide, cytarabine, dactinomycin,
methotrexate
Other Cyclophosphamide (hemorrhagic cystitis);
procarbazine (leukemia); asparaginase*
(pancreatitis)
*Less Bone marrow suppression – “marrow sparing”

42. Prevention or Management of Drug
Induced toxicities
• The toxicities of some anticancer drugs can be
well anticipated and hence be prevented by
giving proper medications
E.g.
1.mesna is given to prevent hemorrhagic cystitis
by cyclophosphamide
2.Dexrazoxane, is used to reduce the risk of
anthracycline-induced cardiomyopathy

43. CRITERIA USED TO DESCRIBE
RESPONSE ARE
• Complete response (complete remission)is the
disappearance of all detectable malignant disease.
• Partial response : is decrease by more than 50% in the sum
of the products of the perpendicular diameters of all
measurable lesions.
• Stable disease : no increase in size of any lesion nor the
appearance of any new lesions.
• Progressive disease : means an increase by at least 25% in
the sum of the products of the perpendicular diameters of
measurable lesions or the appearance of new lesions.