Principles of medical_oncology dr. varun

Principles of Medical Oncology

Dr Varun GoelMEDICAL ONCOLOGISTRAJIV GANDHI CANCER INSTITUTE, DELHI

BASIC TENETS

• Cancer Treatment is multidisciplinary

• The suspicion of cancer is based on clinical acumen

• Diagnosis is based on examination of tissue samples

BASIC TENETS

• Oncology care is for life

• Early stage cancers are more curable than late stage

• Best treatment is often found in clinical trials

CLINICAL ACUMEN

• Cancer, like Syphilis, is the "Great Masquerader“ must be considered in every d/d

• No symptom should be attributable

to cancer without persuasive evidence

eg: Pulmonary insufficiency Meningoencephilits Unexplained pain

Proving the diagnosis

• Cytology from stomach, cervix, bronchus • Biochemical markers

βhCG, Alfa fetoproteins, CA19-9, CA125

• Histological proof

• Always aim to have histological dia-gnosis

Laws of Therapeutics-Loeb

• If what you are doing, is doing good, keep doing it.

• If what you are doing, is not doing good, stop doing it.

• If you do not know what to do, do nothing.• Never make the treatment worse than the

disease.

………………keep doing it.

Physician measures effect of intervention on both tumor and host.

Continue administering a highly active induction treatment?

• Eg: in childhood leukemia an induction treatment followed by shift to mainten-ance therapy with different agents exper-ienced long term remissions.

First law of Loeb does not always apply to

cancer

………………..stop doing it.

• No therapeutic response in 8 weeks of treatment

• A third month is unlikely to be beneficial

Exceptions• Therapies that work slowly• Tumor stasis therapies

• Hippocratic admonition

"Primum non nocere“(first do no harm)

• Curative and subcurative oncology is toxic

• Attempts to abrogate toxicity by reducing

dose will result in a failed regimen

…………….do nothing"

• counsels against uninformed action.

• A rush to judgment or, worse, a rush to do something, anything, can be disastrous

-except oncological Emergency

• Proper goal is

"Maximal life at Maximal quality"

•Never make the treatment worse than the disease.

• In cancer, the dictum is "Primum succerere" (first hasten to help)

Basic Principles

CHEMOTHERAPY

1.Primary Induction treatment- for advanced disease or for cancers for which there are no other effective treatment approaches

2.Adjuvant treatment

Adjuvant chemotherapy is used to treat patients known to be at high risk of recurrence after initial local therapy (surgery, radiation) has removed all evidence of disease

Intent of Therapy

CURATIVE

PALLIATIVE

Curative chemotherapy

• High dose chemotherapy

• Certainty of severe toxicity

• Treatment given to the point of toxicity

Cancers CURABLE with Chemotherapy

Choriocarcinoma

ALL of childhood

Hodgkin's disease

Burkitt's lymphoma

APML

Large Follicular cell lymphoma

Hairy cell leukemia

Embryonal cell carcinoma of testis

SUBCURABLE Cancers

Wilm's tumor

Osteosarcoma

Ewing's sarcoma

Embryonal rhabdomyosarcoma

Small cell carcinoma of lung

Palliative chemotherapy

• Palliative chemotherapy is given without curative in-

tent, but simply to decrease tumor load and increase

life expectancy. For these regimens, a better toxic-

ity profile is generally expected.

• Minimising potential toxicity is the goal

• Try not to compromise on quality of life

• Dose reduction to avoid toxicity is permissible

Adjuvant Chemotherapy

• Adjuvant chemotherapy is used to treat patients known to be at high risk of recurrence after initial local therapy (surgery, radiation) has removed all evidence of disease

• In addition to surgery/radiotherapy• Goal – to eradicate micrometastases• Reduce local and systemic recurrence• Improve overall survival

Proven role of adjuvant CT

Breast

Ovary

Cervix

Colon

Gastric

NSCLC

Head and Neck

Wilms' tumor

Osteogenic

sarcoma

Neo-adjuvant

• Neoadjuvant therapy is given after a histological

diagnosis has been established, but before

definitive surgical/radiation therapy.

• Localised cancer

• Local therapies are less than completely

effective

Neo-adjuvant therapy

Rationale

• Immediate exposure of local and possible distant disease to effective chemotherapy, avoiding the delay introduced by surgery

• Immediate in vivo assessment of chemotherapy responsiveness of the primary tumor, and therefore, of possible nodal or distant micrometastatic disease

Neo-adjuvant therapy

• Reduce the size of primary tumor

• Better chance of complete resection

• Preservation of organ functiono Laryngeal cancero Anal cancero Osteosarcomao Bladder cancer

Proven role of Neo-adjuvant therapy

Anal cancer Bladder cancer Breast cancer Cervical cancer Head and neck

cancer

Lung cancer Ovarian cancer Osteosarcoma Rectal cancer Soft tissue

sarcoma

Cytokinetics

• ‘kinetics’:- Changes in magnitude over time.

Size, shape, velocity etc.

• Changes at cellular levels---- cytokinetics

• Correlation between cytokinetics and clinical

behaviour

Cell proliferation is associated with

generation of tumor heterogeneity

Growth Curve Analysis

• Mathematical model

• Describes the Increase or Decrease of cells

• Summarises the clinical course, emergence

of mutations

• Growth curves proved useful in new

therapeutic approaches

Growth Curve Analysis

30 doublings = 1 billion cells=1 cm3 mass

will take approximately 5 years.

Tumor with 109 is often curable

Tumor with 1012 is usually fatal

Skipper-Wilcox model

• The log-kill model

• Hypothesised the exponential growth kinetics

• Based on murine leukemia cells L1210

• Constant doubling time

Eg:-

12 hours for 100 cells to grow to 200

cells

12 hours for 109 cells to grow to 2 X

109 cells

Skipper model

• Cell kill is proportional, regardless of tumor burden

• Cardinal rule of Chemotherapy • Invariable inverse relation between cell

number and curability was established with Skipper model

Clinical relevance of exponen-tial growth

Cancers with <1 month doubling time • Testicular cancers and Choriocarcinoma

- More responsive to therapy

Cancers with 2 months doubling time• Squamous cell cancers of Head and Neck

- Less responsive to chemo

Cancers with more than 3 months doubling time• Adenocarcinoma colon

- Unresponsive

Faster growth

• Tumor with shorter doubling time

• Means higher fraction of dividing cells

• More responsive to chemo that kills dividing

cells

Slower growth Slow growth due to :-

less number of dividing cells- Impede response to drugs that kill

only dividing cells

more cell loss from apoptosis- Higher rate of mutations- Impede response to drugs due to

resistance

Skipper-Wilcox model in combination chemotherapy

• One log kill= reduction in cell numbers from 106 cells to 105 cells and so on.

• One log kill will kill 90% population of tu-mor cells

Fundametal concepts of combination therapy

• Drug A has one log-kill. (90% cells eliminated, 10% remaining)

• If drug B, also with one log-kill is given next, • Then it will kill 90% of the remaining 10%, making

the total to 99% tumor cells eliminated 99% =2 log-kill.

• To achieve 2 log kill with drug A alone or drug B alone we need to double the dose of A or B.

• This means more cytotoxicity.

• One log kill with A + one log kill with B has achieved

2 log kill

• There was no increased cytotoxicity with the

combination.

• A+B+C (each with one log kill) will reduce tumor

size from 106 cells to 103 cells to 100 cells

• Thereby eradicating the tumor.

• Clinical trials could not replicate this optimistic

predictions. (adjuvant therapy for

micrometastasis in breast cancer)

• Divergence from the model may be due to drug

resistance

Delbruck-Lubria model

• Model to explain the emergence of drug

resistance.

- Bacterial culture based

• Percentage of cells that randomly acquired

denovo resistance of bacteriophage.

Delbruck-Lubria Hypothesis

• More mitosis means more chance of

acquiring a resistant mutations

• More mitosis also means aberrant DNA and

tumor heterogeneity

Goldie-Coldman model

• Delbruck model was re-applied to human

cancer


• When the tumor increase in size by 2 log(100 times), then the possibility of drug resistant mutations is very high

• When the tumor increases in size, the metastatic ability also increases

• Ca breast T= <1 cm, only 17 % axillary mets T=2 cm, 41% axillary mets T=5-10 cm, 68% axillary mets


• A tumor has 90% chance of cure at a size of 105 cells

and certainly incurable by 107 cells.

• Means, tumor larger than 1 cm3 (at a packing ratio of

1:100) will always be incurable with single agent.

• Best strategy is to treat a small tumor as early as

possible

Evidence to the contrary

• Gestational choriocarcinoma and Burkitt's lymphoma• Rapidly growing cancers• Cured with single drugs

• Childhood ALL and GCT of 1010 cells were cured with 2 agent combination.

• Hence, a size of 107 cells , does not always mean incurability


• As many effective drugs to be used as soon as possible (Combination chemotherapy).

• If several drugs cannot be used simultaneously, then they should be used in strict alternating regimen as compared to sequential regiment.

• Chemotherapeutic failure in sequential regimen was assumed due to development of absolute drug resistance


• Breast cancer that regrow after exposure to

adjuvant CMF are NOT universally resistant

to CMF

• A Temporary absolute drug resistance that

reverses over time explains this clinical

phenomena


• Alternating chemotherapy is better than

Sequential chemotherapy.

- AB AB AB better than AAA BBB


• ProMACE-MOPP hybrid was not better than ProMACE full course followed by MOPP in NHL.

• No advantage of CMFVP alternating with VATH over CAF or VATH alone in Ca Breast.

• Sequential application of intensive induction followed by intensive consolidation was better in leukemia


• Applicable to some aspects of cancer biology.

• Several of model predictions were not

sustained by clinical data.

Patterns of Growth

• Exponential pattern of growth :-

• 1,2,4,8,16.... and so on in equal units of time

• Linear pattern of growth :-

• 1, 2, 3, 4,.... and so on in equal units of time

Linear growth 1,2,3,4…..

• 2 years to grow from 1 cell to 1010 cells (10 cm3)

• Another 2 years to double its size (20 cm3)

• Another 2 years to triple its size (30 cm3)

• Unrealistically slow growth for an untreated primary

cancer

• So ??????? linear growth

Exponential growth

• 2 years to grow from 1 cell to 1010 cells (10 cm3)

• Mass will double its size in every 22 days

• Reach a size of 40 cm3 in less than 7 weeks from

diagnosis.

• Incompatible with clinical experience

• So ????????????? exponential growth

Gompertzian growth

• Growth of tumor is EXPONENTIAL to start with and

deviates towards LINEAR, as the tumor becomes

larger.

• This is called DECREMENTAL EXPONENTIAL

growth curve.

Gompertzian model

• In exponential growth model, the doubling time is fixed.

• In Gompertzian growth, doubling time increases as the tumor grows larger.

• Growth fraction peaks when tumor is approx. 37% of its max size

Gompertzian model

Advanced tumor

large tumor mass

low growth fraction

fractional cell kill is small.

• Response to chemo depends on WHERE the tumor is, in its growth phase

Gompertzian model

• Predictions about behaviour of tumors.

• Clinically undetectable tumor- high growth

fraction.

• Fractional cell kill high with the effective dose

of chemo agent.

Norton-Simon model

• Surviving fraction of a tumor after chemotherapy is inversely related to the tumor size at the start

of treatment.

• Tumor regression is greater when tumor size is bigger at the start of treatment

Gompertzian model

Principles of Dose, Schedule and Combination Therapy

Relation between Dose and Effect

Log cell kill be greater with :-

Greater dose intensity - dose intensity. INC. total amount of drug

received - DOSE ESCALATION

Amount of drug received per unit time - DOSE DENSITY- The third approach involves sequential

scheduling of either single agents, which is, in effect,

combination chemotherapy in sequence

Dose Intensity

Dose escalation :-

• Achieved by raising the dose level

Dose density :-

• Achieved by shortening the duration

of treatment

Dose Intensity

• Regimen 1X mg over Y days

• Regimen 22X mg over Y days DOSE ESCAL-

ATION

• Regimen 3X mg over Y/2 days DOSE DENSITY

• Both regimen 2 and 3 are more dose intensive than regimen 1.

Dose Intensity

• Regimen 2 ( 2X mg over Y days)• Regimen 3 (X mg over Y/2 days)

• Dose Intensity of drug delivery in regimen 2= 2X/Y• Dose Intensity of regimen 3= X/ Y/2=2X/Y

• But regimen 2 delivers more total drug (2X) than regimen 3 (X), and hence is superior.

• Regimen 2 is more EFFECTIVE than regimen 3 though both have the same dose intensity.

• But, it is NOT feasible due to life threatening toxicities involved.

• Hence, the next best method to increase the intensity is by increasing the density.

Dose density

A landmark randomized phase 3 trial

Comparing dose-dense versus conventionally scheduled

chemotherapy in the adjuvant treatment of node-positive primary breast cancer (INT C9741).

In this study, Citron et al.21 showed that a dose-dense

schedule in which the anticancer agents doxorubicin,

cyclophosphamide, and paclitaxel were administered

every 2 weeks rather than at the conventional 3-week intervals.

Resulted in significantly improved clinical outcomes with

respect to disease-free survival and overall survival.

Contd

Egs of dose dense regimens metastatic colorectal cancer, extensive-stage

small-cell lung cancer, and poor-prognosis

germ cancer.

Dose density-Sequencial Rx

Limitation of modern combination chemotherapy -- dose

levels of individual drugs are reduced in an effort to limit toxicity when the drugs are used in combination.

A randomized clinical trial by Bonadonna and Zambetti four 3-week cycles of doxorubicin followed by eight 3-week cycles of CMF

In high-risk primary breast cancer (four or more positive lymph nodes).

Results:Improved clinical efficacy in terms of disease-free and overall survival in seq than in alternating schedule of doxorubicin and CMF at the same dose intensity.

Contd

Sledge et al.- sequential versus combination therapy in the Eastern Cooperative Oncology Group E1193 randomized phase 3 Trial

Combination CT in sequence, with doxorubicin and paclitaxel

versus

a combination of the two agents as the first-line treatment

( metastatic breast cancer)

Results:

Combination therapy yielded a superior response rate and time to disease progression but has not yet translated into a survival benefit when compared with sequential single-agent therapy. Such sequential strategies are being tested for treatment of other solid tumors, including colorectal cancer and ovarian cancer.

Summation Dose Intensity

• Relation between Dose intensity and Combination Chemotherapy.

• Efficacy of a combination is related to sum of dose intensities of all the agents used.

Single agent - Choriocarcinoma ,Burkit’s lymphoma

Combination chemotherapy

Advantages

1. Maximal cell kill within the range of toxicity tolerated by the host for each drug.

2. It provides a broader range of interaction between drugs and tumor cells with different genetic abnormalities in a heterogeneous tumor population.

3. It may prevent and/or slow the subsequent development of cellular drug resistance.

THANK U…

Principles of medical_oncology dr. varun

Health & Medicine

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