Docetaxel, in doses ranging from 50–70 mg/m2, was administered for 1 h by drip infusion either just before or after a 5-min bolus i.v. injection of doxorubicin at dosages from 40–50 mg/m2. The sequence of drug administration was switched after the first course in each patient, and the sequence of drug administration thereafter depended on the patient’s choice. Twenty-five patients were initially assessable for toxicity. The MTD in the sequence of doxorubicin after docetaxel was 40 and 50 mg/m2, respectively, with the dose-limiting toxicity of neutropenia. On the other hand, the MTD of the sequence of docetaxel after doxorubicin was 70 and 50 mg/m2, respectively. The dose-limiting toxicities in this sequence were neutropenia and diarrhea. Duration of grade 4 neutropenia in the sequence of docetaxel followed by doxorubicin was significantly longer than that in the alternate sequence (P = 0.0062). However, there was no difference in pharmacokinetic parameters of docetaxel, doxorubicin, and doxorubicinol between the two sequences. The sequence of 50 mg/m2 doxorubicin followed by 60 mg/m2 docetaxel is recommended for subsequent clinical trials for practical reasons.
10. Principles of Chemotherapy: Side Effects of Chemotherapy There are multiple side effects of chemotherapy. Some are common, such as alopecia, neutropenia. Some are rare such as cardiotoxicity. The side effects are generally the consequence of the cytotoxic effect of chemotherapy on normal cells, however they can also be related to the direct toxicity of the drug.
24% of all colon cancers are right sided and will be missed by a flex sig.
Principles of chemotherapy ppt
Dr. R. RAJKUMAR M.D; D.M.Dr. R. RAJKUMAR M.D; D.M.
ASSISTANT PROF.& CONSULTANTASSISTANT PROF.& CONSULTANT
MEDICAL ONCOLOGISTMEDICAL ONCOLOGIST
A cancer, is thought to developA cancer, is thought to develop
from a cell in which the normalfrom a cell in which the normal
mechanisms for control ofmechanisms for control of
growth and proliferation aregrowth and proliferation are
Current evidence supports theCurrent evidence supports the
concept of carcinogenesis as aconcept of carcinogenesis as a
multistage process that ismultistage process that is
genetically regulatedgenetically regulated
Genetic and Molecular Basis of CancerGenetic and Molecular Basis of Cancer
Two major classes of genes are involved inTwo major classes of genes are involved in
carcinogenesis: oncogenes and tumorcarcinogenesis: oncogenes and tumor
suppressor genessuppressor genes
HallmarksHallmarks oof Cancerf Cancer
Target Areas for Therapeutic InterventionsTarget Areas for Therapeutic Interventions
Surgery was the first modality usedSurgery was the first modality used
successfully in the treatment ofsuccessfully in the treatment of
It is the only curative therapy for someIt is the only curative therapy for some
common solid tumors.common solid tumors.
The most important determinant of aThe most important determinant of a
successful surgical therapy are thesuccessful surgical therapy are the
absence of distant metastases and noabsence of distant metastases and no
local infiltrationlocal infiltration..
Microscopic invasion of surroundingMicroscopic invasion of surrounding
normal tissue will necessitatenormal tissue will necessitate
multiple frozen section.multiple frozen section.
Resection or sampling of regionalResection or sampling of regional
lymph node is usually indicated.lymph node is usually indicated.
Surgery may be used for palliation inSurgery may be used for palliation in
patients for whom cure is notpatients for whom cure is not
Has significant role in cancerHas significant role in cancer
E.gE.g familial polyposis coli.familial polyposis coli.
Radiation therapy: is a local modalityRadiation therapy: is a local modality
used in the treatment of cancer .used in the treatment of cancer .
Success depend in the difference inSuccess depend in the difference in
the sensitivity between the tumor andthe sensitivity between the tumor and
normal tissue.normal tissue.
It involves the administration ofIt involves the administration of
ionizing radiation in the form of x-rayionizing radiation in the form of x-ray
or gamma rays to the tumor site.or gamma rays to the tumor site.
Method of delivery: ExternalMethod of delivery: External
beam(teletherapy). Internal beambeam(teletherapy). Internal beam
Radiation therapy is planned andRadiation therapy is planned and
performed by a team of nurses,performed by a team of nurses,
dosimetrists,physician and radiationdosimetrists,physician and radiation
A course of radiation therapy isA course of radiation therapy is
preceded by a simulation session inpreceded by a simulation session in
which low-energy beam are used towhich low-energy beam are used to
produce radiograghic images thatproduce radiograghic images that
indicate the exact beam locationindicate the exact beam location..
Radiation therapy is usually deliveredRadiation therapy is usually delivered
in fractionated doses such as 180 toin fractionated doses such as 180 to
300 cGy per day,five times a week for300 cGy per day,five times a week for
a total course of 5-8 weeks.a total course of 5-8 weeks.
Radiation therapy with curative intentRadiation therapy with curative intent
is the main treatment in limited stageis the main treatment in limited stage
Hodgkin’s disease , some NHL,Hodgkin’s disease , some NHL,
limited stage CA prostate, gynecologiclimited stage CA prostate, gynecologic
tumors & CNS tumortumors & CNS tumor ..
Also can be used in palliative &Also can be used in palliative &
emergency setting.emergency setting.
There are two types of toxicities - acute andThere are two types of toxicities - acute and
long term toxicity.long term toxicity.
Systemic symptoms such as Fatigue , localSystemic symptoms such as Fatigue , local
skin reaction , GI toxicity , oropharyngealskin reaction , GI toxicity , oropharyngeal
mucositis , xerostomia & myelosuppression.mucositis , xerostomia & myelosuppression.
Long-term sequelae: may occur manyLong-term sequelae: may occur many
months or years after radiation therapy.months or years after radiation therapy.
Radiation therapy is known to be mutagenic,Radiation therapy is known to be mutagenic,
carcinogenic ,and teratogenic ,and havingcarcinogenic ,and teratogenic ,and having
increased risk of developing both secondaryincreased risk of developing both secondary
leukemia and solid tumorleukemia and solid tumor..
For decades have been usedFor decades have been used
systemically to treat malignantsystemically to treat malignant
They are administer by specialists inThey are administer by specialists in
nuclear medicine or radiationnuclear medicine or radiation
Radioactive iodine in the from ofRadioactive iodine in the from of 131131
I isI is
effective therapy for welleffective therapy for well
differentiated thyroid cadifferentiated thyroid ca
Strontium-89. Is used for theStrontium-89. Is used for the
treatment of bony metastasis .It is antreatment of bony metastasis .It is an
alkaline earth element in the samealkaline earth element in the same
family as calciumfamily as calcium
Paul Ehrlich 1854 -
• Father of Chemotherapy
• Salvarsan for Treatment
• Nobel Prize 1908
• “Magic Bullet Concept”
Nitrogen mustards were a product ofNitrogen mustards were a product of
the secret war gas programs in boththe secret war gas programs in both
world warsworld wars
In WWII, an explosion at Bar HarborIn WWII, an explosion at Bar Harbor
exposed seamen to mustard gas - theyexposed seamen to mustard gas - they
developed severe marrow anddeveloped severe marrow and
lymphoid hypoplasialymphoid hypoplasia
Led to the useLed to the use of theseof these agents toagents to
treat Hodgkins and non-Hodgkinstreat Hodgkins and non-Hodgkins
lymphomas at Yale in 1943lymphomas at Yale in 1943
In the 1950’s, folic acid wasIn the 1950’s, folic acid was
shown to accelerate theshown to accelerate the
progression of childhoodprogression of childhood
leukemias; led to development ofleukemias; led to development of
folic acid antagonistsfolic acid antagonists
In the 1960’s, combinationIn the 1960’s, combination
chemotherapy for childhoodchemotherapy for childhood
leukemias and Hodgkinsleukemias and Hodgkins
lymphoma began to be usedlymphoma began to be used
Systemic chemotherapy is the mainSystemic chemotherapy is the main
treatment available for disseminatedtreatment available for disseminated
malignant diseases.malignant diseases.
Progress in chemotherapy resulted inProgress in chemotherapy resulted in
cure for several tumors.cure for several tumors.
Chemotherapy usually require multipleChemotherapy usually require multiple
MODES OF CHEMOTHERAPY
PRIMARY CHEMOTHERAPYPRIMARY CHEMOTHERAPY - chemotherapy- chemotherapy
is used as the sole anti-cancer treatment inis used as the sole anti-cancer treatment in
a highly sensitive tumor typesa highly sensitive tumor types
Example – CHOP for Non-HodgkinsExample – CHOP for Non-Hodgkins
ADJUVANT CHEMOTHERAPYADJUVANT CHEMOTHERAPY – treatment is– treatment is
given after surgery to “mop up” microscopicgiven after surgery to “mop up” microscopic
residual diseaseresidual disease
Example – Adriamycin, cyclophosphamideExample – Adriamycin, cyclophosphamide
for breast cancerfor breast cancer
NEOADJUVANT CHEMOTHERAPYNEOADJUVANT CHEMOTHERAPY ––
treatment is given before surgery to shrinktreatment is given before surgery to shrink
tumor and increase chance of successfultumor and increase chance of successful
Example – Adriamycin, ifosfamide forExample – Adriamycin, ifosfamide for
CONCURRENT CHEMOTHERAPYCONCURRENT CHEMOTHERAPY ––
treatment is given simultaneous totreatment is given simultaneous to
radiation to increase sensitivity ofradiation to increase sensitivity of
cancer cells to radiationcancer cells to radiation
Example – Cisplatin, 5-fluourouracil,Example – Cisplatin, 5-fluourouracil,
XRT for head and neck tumorsXRT for head and neck tumors
There is a wide variation in
sensitivity of various cancers
HighHigh IntermediateIntermediate LowLow
LymphomaLymphoma BreastBreast Head and neckHead and neck
LeukemiaLeukemia ColonColon ProstateProstate
Small Cell LungSmall Cell Lung
Non-small cell lungNon-small cell lung
Testicular cancerTesticular cancer PancreaticPancreatic
1. The “Silver Bullet” isn’t out there1. The “Silver Bullet” isn’t out there..
2.2. Conventional chemotherapy targetsConventional chemotherapy targets
have been the cell cycle, microtubuleshave been the cell cycle, microtubules
and DNAand DNA
3. Combination chemotherapy improves3. Combination chemotherapy improves
responses over single agent, but doseresponses over single agent, but dose
intensity must be maintained.intensity must be maintained.
44.. It is better to treatIt is better to treat
micrometastatic diseasemicrometastatic disease
5. Phase I trials define an5. Phase I trials define an
MTD --a Maximum ToleratedMTD --a Maximum Tolerated
Dose - this may not equateDose - this may not equate
to the Maximum Therapeuticto the Maximum Therapeutic
6.6. For classical chemotherapy to beFor classical chemotherapy to be
effective, cell proliferation iseffective, cell proliferation is
required. Indolent (slowlyrequired. Indolent (slowly
growing) cancers are typicallygrowing) cancers are typically
resistant. If therapy isresistant. If therapy is
ineffective, tumor indolenceineffective, tumor indolence
determines survival.determines survival.
7.Almost7.Almost all who die with cancerall who die with cancer
have been treated withhave been treated with
chemotherapychemotherapy ---- thus drugthus drug
resistance is a major cause ofresistance is a major cause of
GROWTH Growth rates are exponential atGrowth rates are exponential at
early stagesearly stages of development andof development and
slowerslower at later stages ofat later stages of
Biological growth follows this characteristicBiological growth follows this characteristic
Initial tumour growth is first order, with
later growth being much slower
Smaller tumour grows slowly but large % of
Medium size tumour grows more quickly but
with smaller growth fraction
Large tumour has small growth rate and
AIM OF COMBINATION
INCREASED EFFICACYINCREASED EFFICACY
Different mechanisms of action Compatible side effects
Different mechanisms of resistance
Rationale for combinationRationale for combination
Different drugs exert their effectDifferent drugs exert their effect
through different mechanismsthrough different mechanisms
and at different stages of the celland at different stages of the cell
cycle, thus maximize cell killcycle, thus maximize cell kill
Decease the chance of drugDecease the chance of drug
Agents Dose Intensity PR (%)* CR (%)*
Cyclophosphamide 1 1 35 0
Methotrexate 1 1 25 0
Fluorouracil 1 1 25 0
Doxorubicin (A) 1 1 50 5
CMF 0.5+0.33+0.33 1.17 50 5
CAF 0.5+0.7+0.33 1.53 75 10
* Patients with overt metastases and no prior chemotherapy except in the
PR = partial response
CR = complete response
(“Cancer Medicine”, Holland and Frey (eds.), 5th
More is better, to a point!
Advanced Hodgkin’s Disease
Careful Sequencing is Critical
40 mg/m2 50 mg/m2
50 mg/m2 70 mg/m2
Itoh et al. Study of Sequence Switching of Administration
Clin. Cancer Res 6:4082-4090, 2000
Adjuvant Chemotherapy Improves
Osteosarcoma: Sarcoma of the bone
1970’s: Surgery if no evidence of metastatic
One-half developed metastatic disease,
Usually within 6 mos of surgery
20% 5 year survival.
Thus:80% had micrometastatic disease.
With adjuvant chemotherapy:
60-70% long-term survival
adjuvant chemotherapy improves
Breast Cancer C CMF ∆
1970’s: 3 yr RFS 1 -3 Nodes+ 64% 78% 39%
>3 Nodes+ 44% 49% 9%
CAF vs. CMF: 2% - 12% improvement reported
Widely adopted: Adriamycin + Cytoxan
Increasingly, followed by Taxol
Interphase Prophase Metaphase
Anaphase Interphase Cytokinesis
STAGES OF MITOSIS:
After completion of mitosis, the resulting daughterAfter completion of mitosis, the resulting daughter
cells have two options:cells have two options:
(1) they can either enter G1 & repeat the cycle or(1) they can either enter G1 & repeat the cycle or
(2) they can go into G0 and not participate in the cell(2) they can go into G0 and not participate in the cell
Growth fraction - at any particular time some cellsGrowth fraction - at any particular time some cells
are going through the cell cycle whereas other cellsare going through the cell cycle whereas other cells
are resting.are resting.
The ratio of proliferating cells to cells in G0, isThe ratio of proliferating cells to cells in G0, is
called the growth fraction.called the growth fraction.
A tissue with aA tissue with a large percentage of proliferatinglarge percentage of proliferating
cellscells & few cells in& few cells in G0G0 has ahas a high growth fraction.high growth fraction.
Conversely, a tissue composed ofConversely, a tissue composed of mostly of cells inmostly of cells in
G0G0 has ahas a low growth fractionlow growth fraction..
MECHANISMS OF CHEMOTHERAPY
Damage the DNADamage the DNA of the affected cancerof the affected cancer
cells. It is not always possible to be selective, butcells. It is not always possible to be selective, but
selectivity is the ultimate goal of any drug.selectivity is the ultimate goal of any drug. e.g.e.g.,,
cisplatin (Platinol®), daunorubicin (Cerubidine®),cisplatin (Platinol®), daunorubicin (Cerubidine®),
doxorubicin (Adriamycin®), and etoposidedoxorubicin (Adriamycin®), and etoposide
Inhibit the synthesis of new DNAInhibit the synthesis of new DNA
strands to stop the cell from replicating, becausestrands to stop the cell from replicating, because
the replication of the cell is what allows the tumorthe replication of the cell is what allows the tumor
to grow.to grow. e.ge.g..,, methotrexate (Abitrexate®),methotrexate (Abitrexate®),
mercaptopurine (Purinethol®), fluorouracilmercaptopurine (Purinethol®), fluorouracil
(Adrucil®), and hydroxyurea (Hydrea®).(Adrucil®), and hydroxyurea (Hydrea®).
Stop the mitotic processesStop the mitotic processes of a cell.of a cell.
Stopping mitosis stops cell division (replication) ofStopping mitosis stops cell division (replication) of
the cancer and may ultimately halt the progressionthe cancer and may ultimately halt the progression
of the cancer.of the cancer. e.g.e.g., Vinblastine (Velban®),, Vinblastine (Velban®),
Vincristine (Oncovin®)Vincristine (Oncovin®) and Pacitaxel (Taxol®).and Pacitaxel (Taxol®).
Cytotoxic agent can be roughlyCytotoxic agent can be roughly
categorized based on theircategorized based on their
activity in relation to the cellactivity in relation to the cell
p h a s e n o n s p e c ific . p h a s e s p e c ific
c y to to x ic d r u g
What is the difference between phaseWhat is the difference between phase
specific & phase non specific?…..specific & phase non specific?…..
Phase non-specific:Phase non-specific:
The drugs generally have a linearThe drugs generally have a linear
dose-response curve(dose-response curve(↑↑ the drugthe drug
administration ,theadministration ,the ↑↑ the fraction ofthe fraction of
cell killed).cell killed).
Phase specific:Phase specific:
Above a certain dosage level,furtherAbove a certain dosage level,further
increase in drug doesn’t result inincrease in drug doesn’t result in
more cell killing.but you can playmore cell killing.but you can play
with duration of infusion.with duration of infusion.
Two Broad Classes of
Cytotoxic agentsCytotoxic agents
Cisplatin – causes DNA damageCisplatin – causes DNA damage
5-Fluourouracil – blocks enzymes5-Fluourouracil – blocks enzymes
necessary for RNA and DNA synthesisnecessary for RNA and DNA synthesis
Docetaxel – inhibits microtubuleDocetaxel – inhibits microtubule
Targeted therapiesTargeted therapies
Erlotinib – small molecule inhibitor theErlotinib – small molecule inhibitor the
EGFR tyrosine kinaseEGFR tyrosine kinase
Cetuximab – antibody that binds to EGFRCetuximab – antibody that binds to EGFR
PLANNING DRUG DOSES
- based on body surface area- based on body surface area
- differ between children and adults- differ between children and adults
- adjusted for people who are elderly, have poor- adjusted for people who are elderly, have poor
nutritional status, have already taken or takingnutritional status, have already taken or taking
other medications, have already received orother medications, have already received or
are currently receiving radiation therapy, have loware currently receiving radiation therapy, have low
blood cell counts, or have liver or kidney diseasesblood cell counts, or have liver or kidney diseases
PLANNING DRUG DOSES
Schedule (Cycles)Schedule (Cycles)
- A cycle = one dose followed by several- A cycle = one dose followed by several
days or weeks without treatment for normaldays or weeks without treatment for normal
tissues to recover from the drug’s side effectstissues to recover from the drug’s side effects
The number of cycles = based on the type andThe number of cycles = based on the type and
stage of cancer, and side effectsstage of cancer, and side effects
CONSIDERATIONS FOR DOSE
Platelet - 7-10 daysPlatelet - 7-10 days
Red blood cell - 120 daysRed blood cell - 120 days
Neutrophils - 6-12 hoursNeutrophils - 6-12 hours
Time from Stem Cell to Mature NeutrophilTime from Stem Cell to Mature Neutrophil
~7-10 days~7-10 days
DECIDING ON TREATMENT
As short as possibleAs short as possible
Recovery of bone marrowRecovery of bone marrow
Supplies mature cells for 8-10 daysSupplies mature cells for 8-10 days
Onset 9-10th daysOnset 9-10th days
Lowest (nadir) 14-18Lowest (nadir) 14-18thth
Recovery by day 21-28.Recovery by day 21-28.
Usual schedule is q21-28 days.Usual schedule is q21-28 days.
Every chemotherapeutic will have someEvery chemotherapeutic will have some
deleterious side effect on normal tissue .deleterious side effect on normal tissue .
E.G; Myelosuppression,nausea&vomiting,E.G; Myelosuppression,nausea&vomiting,
Stomatitis,and alopecia are the mostStomatitis,and alopecia are the most
frequently observed side effects.frequently observed side effects.
SIDE EFFECTS OF CHEMOTHERAPYSIDE EFFECTS OF CHEMOTHERAPY
CRITERIA USED TO
DESCRIBE RESPONSE ARE:
Complete response (complete remission)is(complete remission)is
the disappearance of all detectablethe disappearance of all detectable
malignant disease.malignant disease.
Partial response : is decrease by more than: is decrease by more than
50% in the sum of the products of the50% in the sum of the products of the
perpendicular diameters of all measurableperpendicular diameters of all measurable
Stable disease : no increase in size of any: no increase in size of any
lesion nor the appearance of any newlesion nor the appearance of any new
Progressive disease : means an increase by: means an increase by
at least 25% in the sum of the products ofat least 25% in the sum of the products of
the perpendicular diameters of measurablethe perpendicular diameters of measurable
lesion or the appearance of newlesion or the appearance of new lesions.lesions.
Methods to increase
the efficacy of
standard dosingstandard dosing
high dosehigh dose
Many hormonal antitumor agents are functional agonist orMany hormonal antitumor agents are functional agonist or
antagonist of the steroid hormone family.antagonist of the steroid hormone family.
Aromatase inhibitor:Aromatase inhibitor:
Gonadotropin-releasing hormone agonists:Gonadotropin-releasing hormone agonists:
Somatostatin analogues:Somatostatin analogues:
Are frequently used in combination regimen forAre frequently used in combination regimen for
the treatment of lymphocytic leukemia andthe treatment of lymphocytic leukemia and
They function by binding to glucocorticoid-They function by binding to glucocorticoid-
specific receptors present in lymphoid cells andspecific receptors present in lymphoid cells and
initiate programmed cell deathinitiate programmed cell death
They most commonly used agent areThey most commonly used agent are
Flutamide :Flutamide :
Effectively blocks the binding of androgen toEffectively blocks the binding of androgen to
its receptor in the periphral tissue .its receptor in the periphral tissue .
It is used in the treatment of disseminatedIt is used in the treatment of disseminated
prostate caprostate ca
New technology and drugs that allow the
cancer treatment to “target” a certain cancer cell
by interfering with the natural functions of tumor
How they work
They “target” specific parts of a cancer cell or
its actions; hand in a glove analogy
What it means in cancer treatment
Potentially fewer side effects
Monoclonal antibodiesMonoclonal antibodies: proteins that trigger the: proteins that trigger the
body’s pathways involved in cancer growth tobody’s pathways involved in cancer growth to
fight cancer more effectively.fight cancer more effectively.
EGFREGFR: family of receptors found on surface of: family of receptors found on surface of
normal and cancer cells that bind with annormal and cancer cells that bind with an
epidermal growth factor (EGF) causing cells toepidermal growth factor (EGF) causing cells to
Tyrosine Kinase InhibitorsTyrosine Kinase Inhibitors: Part of the cell that: Part of the cell that
signals it to divide and multiply; enhances cellsignals it to divide and multiply; enhances cell
growth. Still investigationalgrowth. Still investigational
People with cancer are living longerPeople with cancer are living longer
The focus is on quality of life in addition toThe focus is on quality of life in addition to
People surviving cancer want to live normal livesPeople surviving cancer want to live normal lives
New treatments of various kinds are available andNew treatments of various kinds are available and
there is no need to sufferthere is no need to suffer