Certain principles govern the application of therapiesThese were enunciated more than half centuary ago by robert f. loebThese simple rules have nearly universal applicabilty but must be tempered
In many circumstances
Fraction of deviding cells seems to decrease possibly in.proportion as a consequence of fractal geometryBiologically basis for this type of growth is still unclear
Fractal geometric pattern means that no. Of cells is proportional to tumor volumeTumor with mass dimension closer to 3 more malignant while around >2.7 benign If cells are.responding to concentration of growth factors and conc. Is proportional to no. Of cells deviding by their total volume this explains gompertzian.growth
Distinction between skipper wilcox and Norton Simon model is that in gompertzian growth unlike exponential growth growth rate of tumor is always changing
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 diagnosis
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 bothtumor and host.Continue administering a highly active induction treatment? • Eg: in childhood leukemia an induction treatment followed by shift to maintenance therapy with different agents experienced 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 PrinciplesCHEMOTHERAPY1.Primary Induction treatment- for advanced disease or for cancers for which there are no other effective treatment approaches2.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
Curative chemotherapy• High dose chemotherapy• Certainty of severe toxicity• Treatment given to the point of toxicity
Cancers CURABLE with Chemo therapy Choriocarcinoma ALL of childhood Hodgkins disease Burkitts lymphoma APML Large Follicular cell lymphoma Hairy cell leukemia Embryonal cell carcinoma of testis
SUBCURABLE Cancers Wilms tumor Osteosarcoma Ewings sarcoma Embryonal rhabdomyosarcoma Small cell carcinoma of lung
Palliative chemotherapy• Palliative chemotherapy is given without curative intent,but simply to decrease tumor load and increase lifeexpectancy. For these regimens, a better toxicity profileis 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 NSCLC Ovary Head and Neck Cervix Wilms tumor Colon Osteogenic Gastric 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 therapyRationale• 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 function o Laryngeal cancer o Anal cancer o Osteosarcoma o Bladder cancer
Proven role of Neo-adjuvant therapy Anal cancer Lung cancer Bladder cancer Ovarian cancer Breast cancer Osteosarcoma Cervical cancer Rectal cancer Head and neck Soft tissue cancer sarcoma
• ‘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 Analysis30 doublings = 1 billion cells=1 cm3 mass will take approximately 5 years.Tumor with 109 is often curableTumor 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 exponential 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 incombination chemotherapy• One log kill= reduction in cell numbers from106 cells to 105 cells and so on.• One log kill will kill 90% population of tumor 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 thecombination.• 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
Goldie-Coldman model• 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
Goldie-Coldman model• 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 Burkitts 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
Goldie-Coldman model• 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
Evidence to the contrary• 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
Goldie-Coldman model• Alternating chemotherapy is better than Sequential chemotherapy. - AB AB AB better than AAA BBB
Evidence to the contrary• 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
Goldie-Coldman model• 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 chemotherapyis inversely related to the tumor size at the startof treatment.•Tumor regression is greater when tumor size isbigger at the start of treatment
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 schedulingof either single agents, which is, in effect,combination chemotherapy in sequence
Dose IntensityDose escalation :- • Achieved by raising the dose levelDose density :- • Achieved by shortening the duration of treatment
Dose Intensity• Regimen 1 X mg over Y days• Regimen 2 2X mg over Y days DOSE ESCALATION• Regimen 3 X 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 d ose 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 densityA landmark randomized phase 3 trialComparing 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.
ContdEgs of dose dense regimens metastatic colorectal cancer, extensive-stage small-cell lung cancer, and poor-prognosis germ cancer.
Dose density-Sequencial RxLimitation 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.
ContdSledge et al.- sequential versus combination therapy in the Eastern Cooperative Oncology Group E1193 randomized phase 3 TrialCombination CT in sequence, with doxorubicin and paclitaxel versusa 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 lymphomaCombination chemotherapyAdvantages1. 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.