Dr. Jyotiman Nath presented on the history and development of cancer chemotherapy. Some key points include:
- Chemotherapy originated in the early 20th century with Paul Ehrlich's work on "magic bullets" to treat infections. Sidney Farber is considered the father of modern chemotherapy.
- During World Wars I and II, exposure of soldiers to mustard gas led to the observation that alkylating agents suppressed bone marrow, laying the foundations for using similar agents to treat cancers.
- In the 1940s and 50s, drugs like methotrexate and combinations of drugs were used successfully to treat various cancers, representing major advances in the field.
- Current chemotherapy typically involves combinations of
2. The term “Chemotherapy” was
coined by Paul Ehrlich in early 20th
century – ‘magic bullets’ in the
treatment of bacterial infections
Sidney Farber – father of ‘modern
chemotherapy’
3. The origin of cancer chemotherapy.....
WW (I) exposure of military to mustard gas led to the
observation that alkylating agents caused marrow and
lymphoid hypoplasia wich is further studied during
WW(II)
This observation led to the direct application of such
agents to patients with Hodgkin’s disease and
lymphocytic lymphomas at Yale Cancer Center in 1943
Luis Goodman and Alfred Gillmen demonstrated it for
the first time.
4. 1948, Sydney Farber successfully used Antifolates to induce
remission in children with ALL.
1955, National chemotherapy program begins at National cancer
institute, a systematic programme for drug screening.
1958, Roy Hertz and Min Chiu Li demonstrated Methotrexate
as a single best agent for choriocarcinoma, the first solid
tumour that can be cured by chemotherapy.
1959, FDA approved the alkylating agent, Cyclophosphamide
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. • Neoadjuvant chemotherapy (primary or induction):
given before definitive surgical therapy (in the context of
locally extensive disease with a risk of distant
micrometastatic disease)
• Adjuvant chemotherapy: used to treat tumors with
high risk of recurrence after initial local therapy (surgery
and RT) has removed all evidence of disease
Modalities of Cancer Chemotherapy
8. • Multimodality therapy: chemotherapy and/or
radiation therapy after a tumor has been incompletely
removed
Concurrent Chemoradiation
Chemotherapy and Hormonal therapy
Biochemotherapy (Chemotherapy and
Immunotherapy)
Chemotherapy and Targeted therapy
• Palliative chemotherapy Zoledronic acid for
skeletal metastasis
9. Presently used in 4 clinical setting....
Primary induction treatment for advance disease or
cancers for which no other effective treatment
available
As primary or neoadjuvant treatment for patients
with localized disease for which local forms of therapy
is ineffective
Adjuvant treatment for early stage disease following
local forms of treatment
Direct instillation into tumour site
10. Conventional chemotherapy targets have been the cell
cycle, microtubules and DNA
Rationale for combination chemotherapy
•Different drugs exert their effect through different
mechanisms and at different stages of the cell cycle, thus
maximize cell kill
•Decease the chance of drug resistance
Principles........
11. For classical chemotherapy to be effective, cell
proliferation is required. Indolent (slowly growing)
cancers are typically resistant.
It is better to treat micrometastatic disease
Maximum Tolerated Dose - this may not equate to
the Maximum Therapeutic Dose
12. The only principle regarding dosage is
that, dose must be adjusted to the
individual patient, and that nothing can
or will supersede clinical experience, and
careful study, combined with good
judgement.
13. PRINCIPLES FOR COMBINATION
CHEMOTHERAPEUTIC REGIMENS....
All drugs must have single-agent activity
Drugs should have no overlapping toxicity
Drugs should have different mechanisms of action
Drugs should have different mechanisms or patterns of
resistance
Drugs should be given in optimum dose and schedule to
optimize dose intensity/dose density
Drugs should be individually titrated in individual patients to
end-organ toxicity to optimize adherence to schedule
14. Primary chemotherapy: cancers for which chemo
is primary treatment modality
Acute Leukemia
NHL
HL
Germ cell tumour
Primary CNS lymphoma
Ovarian Carcinoma
Small cell lung CA
Wilms tumour
Embryonal rhabdomyosarcoma
15. Neoadjuvant Chemotherapy: Cancers for which
Neoadjuvant chemo is usefull for locally advanced
disease...........
Anal Cancer
Bladder Cancer
Breast Cancer
Cervical Cancer
Gastroesophageal CA
Non Small Cell lung CA
Head and Neck CA
Ovarian CA
Osteogenic Sarcoma
Rectal CA
Soft tissu Sarcoma
16. Chemosensitivity of tumors
► high
ALL
Hodgkin’s
disease
NHL
testicular cancer
SCLC
Wilms’ tumor
medium
ovarian cancer
breast cancer
osteosarcoma
head & neck
cancer
multiple myeloma
bladder cancer
colorectal cancer
low
NSCLC
cervical cancer
endometrial
cancer
adult soft
tissue sarcoma
malignant
melanoma
liver cancer
pancreatic
cancer
17.
18. Phases of cell cycle
G1 - primary growth
phase
S – synthesis; DNA
replicated
G2 - secondary growth
phase
collectively these 3 stages are
called interphase
M - mitosis
C - cytokinesis
20. G0 phase (resting stage): The cell has not yet
started to divide. Depending on the type of
cell, G0 can last from a few hours to a few years.
When the cell gets a signal to reproduce, it moves
into the G1 phase:
G1 phase During this phase, the cell starts
making more proteins and growing larger, so the
new cells will be of normal size. This phase lasts
about 18 to 30 hours.
21. S phase: In the S phase, the chromosomes
containing the genetic code (DNA) are copied so that
both of the new cells formed will have matching
strands of DNA. It lasts about 18 to 20 hours.
G2 phase: The cell checks the DNA and gets ready
to start splitting into 2 cells. This phase lasts from 2
to 10 hours.
M phase (mitosis): In this phase, which lasts only
30 to 60 minutes, the cell actually splits into 2 new
cells
23. Control of cell cycle- by special proteins and enzymes that
act as switches
G1 checkpoint- stop, pause or go into S phase some cells
stop permanently
G2 checkpoint- will
cell divide?
M checkpoint-
formation of new cells
24. G1 checkpoints
Rb prevents cell moving into S phase by binding to a transcription
factor
When Rb is phoshporylated it cannot bind so cell can move into S
phase
p53 prevents damaged from dividing (by inhibiting Rb pathway)
Abnormalities in both genes are associated with hereditary forms
of cancer
26. Cell cycle non-selective agents:
Introduces mutations into resting DNA
1. Alkylating agents
2. DNA intercalating agents (spindle poisons -
interferes with tubulin polymerization)
Cell cycle selective agents:
Antimetabolites of DNA synthesis
27. DNA synthesis
Antimetabolites
DNA
DNA transcription DNA duplication
Mitosis
Alkylating agents
Spindle poisons &
Microtuble Stablizers
Intercalating agents
Sites of Action of Cytotoxic Agents at Cellular
Level
29. Alkylating agents
They directly damage DNA to prevent the cancer
cell from reproducing
Cell cycle-specific, but not phase-specific
kills a fixed percentage of
cells at a given dose
30. •First chemotherapyeutic agent used in man
•Prototype alkylating agent
•Main toxicity comes from DNA cross linkage
Nitrogen Mustard
Cyclophosphamide
Mechlorethamine
Uramustine
Melphalan
Chlorambucil
Ifosfamide
31. Cyclophosphamide
alkylation of DNA through the formation of
reactive intermediates
oral bioavailability 100%
T1/2 3-10 hrs
metabolism:
microsomal hydroxylation
hydrolysis to phosphoramide mustard and acrolein
Main side effect is myelosupression
Mesna is used to prevent Toxicity
32. PLATINUM ANALOGUES
Cisplatin, carboplatin, oxaliplatin
Cisplatin is the cornerstone drug in the modern
management of head and neck cancer
Carboplatin is superior to cisplatin due to less
vomitting,renal and less otologic complication, BUT it
is more marrow suppressive agent than Cisplatin
33. They interfere with DNA and RNA growth by
substituting for the normal building blocks of RNA and
DNA.
These agents damage cells during the S phase
Commonly used to treat......
•leukemias,
•cancers of the breast
•ovary,
•intestinal tract,
as well as other types of cancer.
Antimetabolites
35. Antitumor Antibiotics
Cell cycle non-specific agents
Variety of mechanisms: prevents DNA replication,
RNA production,
or both
Anthracyclines
Anthracenediones
Actinomycin D (dactinomycin) – DNA intercalator,
inhibits topoisomerase II also
Bleomycin – inhibits DNA synthesis, G2-phase
specific
Mitomycin C – functions as alkylator
36. Interfere with enzymes involved in DNA replication.
These drugs work in all phases of the cell cycle
Anthracyclines....
•Daunorubicin
•Doxorubicin (Adriamycin)
•Epirubicin
•Idarubicin
Anti-tumour antibiotics that are not anthracyclines
include:
· Actinomycin-D
· Bleomycin
· Mitomycin-C
37. Topoisomerase inhibitors
DNA topoisomerase enzymes alters DNA topology
by causing and resealing DNA breaks
Topoisomerase I - relaxes supercoilded DNA
Topoisomerase II - catalyzes double-stranded
breaking and resealing of DNA
Topoisomerase I inhibitors
•Topotecan
•Irinotecan
Topoisomerase II inhibitors
•Etoposide
•Teniposide.
•Mitoxantrone
Epipodophylotoxins
38. Antimicrotubule (Mitotic spindle) Agents
Vinca Alkaloids
• Vincristine
• Vinblastine
• Vinorelbine
• Vindesine
Plant alkaloids and other compounds derived from natural
products.
They can stop mitosis or inhibit enzymes from making proteins
needed for cell reproduction.
Work during the M phase of the cell cycle but can damage cells
in all phases.
Taxanes
•Paclitaxel
•Docetaxel
Estramustine (combination of estradiol and
non-nitrogen mustard)
Newer antitubular drug
Dolastatin
39. Miscellaneous agents
• Bleomycin – inhibits DNA synthesis, G2- phase specific
• Asparaginase – purified from E. coli &/or Erwinia, hydrolyses
asparagine, inhibits protein synthesis
• Interferons – antitumor, antiproliferative, inhibits
angiogenesis, regulated differentiation, NK cell activation
• Interleukins – IL2 stimulates growth of activated T cells
40. Drugs that block the growth and spread of
cancer by interfering with specific molecules
involved in tumour growth and progression.
Targeted Therapy
The primary goal of targeted therapy is to
fight cancer cells with more precision and
potentially fewer side effects.
42. Monoclonal antibodies
• Relative selectivity for tumor tissue
• Relative lack of toxicity
• Various radioactive and chemotherapeutic agents can
be conjugated to monoclones
Drugs-
Immunoconjugates - Plant toxins,
Bacterial toxins
Radioconjugates –Tositomumab,
Ibritumumab
44. Hormonal therapy is one of the major modalities of
medical treatment for cancer
Hormonal therapy
It involves the manipulation of the endocrine
system through exogenous administration of
specific hormones, particularly steroid hormones, or
drugs which inhibit the production or activity of such
hormones
45. Used for several types of cancers derived from
hormonally responsive tissues, including
the breast, prostate, endometrium, and adrenal cortex.
May also be used in the treatment of paraneoplastic
syndromes.
Most familiar example of hormonal therapy
in oncology is the use of the selective estrogen-
response modulator tamoxifen for the treatment
of breast cancer, although another class of hormonal
agents, aromatase inhibitors, now have an expanding
role in that disease.
49. Dosage calculation in oncology
• Body surface area
– derived in 1916 by Du Bois
– reduce the interpatient variability of drug
exposure and, hence, sideeffects
• AUC (carboplatin)
– Dose (mg) = Target AUC (mg/mL/min) x [GFR (mL/min) + 25]
• Fix dosing
50. Dosages of drugs should be adjusted for
people who:
· Are elderly
· Have poor nutritional status
· Are obese
· Have already taken taking other medicines
· Have already receiving radiation therapy
· Have low blood cell counts
· Have liver or kidney diseases
51. Chemotherapy is generally given at regular
intervals called cycles.
A cycle may involve a dose of one or more drugs
followed by several days or weeks without treatment
This gives normal cells time to recover from the
drug’s side effects.
Planning Chemo shedules
58. Visceral Stimuli Chemoreceptor
trigger zone
Vestibilar input
Dopamine and
serotonin
released
Dopamine and
serotonin
released
Histamin and
acetylcholine
released
Medullary vommiting center stimulated
Nousea and vommiting
Proposed Pathways for CINV
59. Increased afferent input to
the chemoreceptor trigger
zone and vomiting center
Chemotherapy
Cell damage
Higher CNS centers
Release of neuroactive
agentsActivation of vagus
and splanchnic nerves
Small
intestine
Chemoreceptor trigger zone
Medulla
oblongata
Vomiting center
60. Emetogenic Risk of different drugs
High risk(>90%)
•CISPLATIN
•CARMUSTINE
•CYCLOPHOSPHAMIDE
(>1.5 gm/m2)
•STREPTOZOCIN
•DOCARBAZINE
•MECHLORETHAMINE
Moderate risk(30-90%)
•CARBOPLATIN
•CYCLOPHOSPHAMIDE
(< 1.5 gm/m2)
•DOXORUBICIN
•DANORUBICIN
•IFOSFAMIDE
•IRINOTECAN
•OXALIPLATIN
62. Aprepitant Administration
*Given for three days as part of a regimen that
includes a 5-HT3 antagonist and a
corticosteroid
*Recommended dose
125 mg po 1 hour prior to chemotherapy
80 mg daily in the morning on days 2 and 3
*Supplied in 125- and 80-mg capsules
71. Patients must be hydrated before, during, and post drug
administration.
Usual approach is to give at least 1 liter before and 1 liter
post drug treatment of 0.9% sodium chloride with 20 mEq
of KCl and 4 cc MgS04
With higher doses of drug, more aggressive hydration
should be considered with at least 2 liters of fluid
administered before drug
In this setting, urine output should be greater than 100
cc/hr.
Furosemide diuresis may be used after every 2 liters of
fluid
77. Sterility in Men
• Procarbazine most toxic
• Cyclophosphamide [ 9 gm ] generally reversible
• Chlorambucil [ 400 mg ]
• Methotrexate
• Vincristine or vinblastine
• Doxorubicin
• MOPP-like regimens infertility is universal by the third
cycle
• Only 5% to 15% ever regain effective spermatogenesis
78. Teratogenic effects
• Both men and women should be strongly
counseled to avoid pregnancy during active
cancer treatment, when the risks of both
teratogenesis and mutagenesis are highest
• 5-
fluorouracil, cyclophosphamide, busulfan, a
nd chlorambucil anthracyclines . Cis-retinoic
acid thalidomide
79. Tumor Lysis Syndrome
• Large numbers of tumor cells are destroyed
rapidly, resulting in intracellular contents being
released into the bloodstream faster than the body
can eliminate them.
• Hyperkalemia is a common finding
• Collaborative management includes:
– Prevention
– Hydration
– Drug therapy (Allopurinol)
80. Drug Resistance
• The main obstacle to the clinical efficacy of
chemotherapy is the development of drug
resistance.
• Complex and multifactorial, but main causes of
drug resistance are probably now understood
• Inadequacy of tumor vasculature, leading to poor
exposure to chemotherapeutic agents
81.
82. Clinical Endpoints in Evaluating Response to
Chemotherapy
• Complete Response (CR)
– Relapse-free survival after stopping treatment
• Partial Response (PR)
– At least a 50% reduction in measurable tumor mass
• Progressive Disease (PD)
– > 25% increase in one or more lesions
• Stable Disease (SD)
– Neither PR nor PD (no changes)
83. • MRI is commonly used to see the response after
chemotherapy in solid malignancy
• MRI does not always reflect tumour response after
chemotherapy. Therefore, it is necessary to explore
additional parameters to more accurately evaluate
tumour response for the subsequent clinical
determination about radiotherapy or radical
surgery
• In such cases PET Scan Plays a important role in
clinical evaluation: 18FDG- PET
84. Monitoring of serial biomarker for evaluating
response in certain cancers like
*CA 125 for Ovarian Carcinoma
*PSA for Prostate CA
*hCG and AFP for Testicular CA
CT based Tumour density assesment gained some
support in evaluating treatment response in cases
of GIST
85. Besides all these……..
•Routine clinical evaluation for known side
effects of specific dugs
•Routine check up of LFT,RFT, Serum
Electrolytes etc.
are of paramount important during
the course of Chemotherapy treatment
86. It is easy to kill cancer cells, but
the challenge is keeping the
patient alive with less morbidity
at the same time…..!