Principles of Chemotherapy and Hormone Therapy

1. Principles of Chemotherapy and Hormone Therapy DMED 525 Scott North, MDApril 26, 2011

2. Overview • General Principles • Chemotherapy • Drug classes • Dosing • Resistance • Combination treatment • Hormone therapy • General information • Types of agents and administration • Conclusion

3. General Principles • Three major modalities exist to treat cancer • Surgery • RT • Drugs (chemo and hormones) • Surgery and RT are local treatments • Around 50% of cancers are systemic • Drugs are administered either parenterally or orally if well absorbed by GI tract

4. General Principles • Curative therapy • Drugs used alone (hematologic cancers) • Adjuvant therapy to RT or surgery • More willing to ask patients to endure side effects because the potential gain is great • Palliative therapy • Cure not possible • Prolongation of life and improvement in QOL • Have to justify the side effects of treatment

5. General Principles • Adjuvant Therapy • Any therapy given in conjunction with the main modality of treatment • E.g. chemo after surgery for breast cancer • Persistent microscopic tumour cells may have been left behind by the primary modality of treatment • Adjuvant treatment mops them up while still microscopic before they can regrow into incurable, metastatic disease

6. General Principles • Metastatic Therapy • Treatment given in the metastatic setting • Usually cure isn’t possible • Notable exceptions include testicular cancer, gestational trophoblastic neoplasia, Ewing’s sarcoma • Goal is improving quality and quantity of life

7. Chemotherapy • Most chemo agents affect more rapidly dividing cells • Tumours growing more rapidly and having relatively few cells in G0 will be more readily killed • Rapidly dividing normal tissues more at risk of damage and, thus, this explains many of the side effects we see • Bone marrow suppression, hair loss, GI tract

8. Chemotherapy • Most agents don’t kill the cell directly • Create irreparable damage to vital structures (DNA, RNA, critical proteins) • Cell can’t fix itself and as such dies • Apoptosis: programmed cell death • The cell recognizes it has an unfixable problem and has a lethal injury • It dies rather than propagate the injury

9. ChemotherapyDrug Classes • Several different classes of agents • All kill cancer cells by different mechanisms of action • Allows you to mix and match your chemo for greater efficacy and less toxicity • Some drugs have multiple mechanisms of action

10. Chemotherapy Drugs • DO NOT memorize mechanisms of action for chemotherapy drugs • Understand basic principles of how chemotherapy works • I WILL NEVER ASK YOU HOW ANY CHEMOTHERAPY DRUG WORKS

11. ChemotherapyDrug Classes • Alkylating agents • E.g. cyclophosphamide, melphalan • Compounds react with electron rich areas of the cell • DNA tends to react and has adducts added to it and/or crosslinking • DNA is damaged and the cell can’t fix it • Cell undergoes apoptosis

12. ChemotherapyDrug Classes • Platinum analogs • E.g. cisplatin, carboplatin, oxaliplatin • Complex mechanisms of action • Distortion or DNA strands, crosslinks across and between strands • DNA can’t replicate and cell dies

13. ChemotherapyDrug classes • Antimetabolites • E.g. methotrexate, 5-fluorouracil • Drugs interfere with critical metabolic pathways • Folate metabolism, purine and pyrimidine synthesis • Cell can’t proceed because necessary building blocks are missing • DNA replication fails

14. ChemotherapyDrug Classes • Topoisomerase II inhibitors • E.g. etoposide, irinotecan • Topoisomerase II is an essential enzyme in DNA coiling/uncoiling to allow replication • DNA gets nicked and can’t repair itself • Can’t replicate DNA and cell can’t divide

15. ChemotherapyDrug classes • Antimicrotubule agents • E.g. paclitaxel, docetaxel, vincristine • Microtubules are critical for cell division • Chromosomes on metaphase plate • Drugs can either prevent tubules from forming or prevent them from disassembling • End result is the cell cycle gets arrested

16. Chemotherapy dosing • Chemotherapy damages normal as well as cancer cells • Normal cells need time to recover • Chemo is usually given cyclically with time for normal tissues to recover • Each administration is called a cycle • Optimum timing between cycles and dose of drug to be given are determined from preclinical models and human trials

17. Chemotherapy dosing • Chemotherapy kills actively dividing cells • A certain proportion of cells are dividing at any time; as cells die off, others come out of G0 and enter the cell cycle • Chemotherapy kills a proportion of cells each cycle, not an absolute number • Most of the killing occurs in the first few cycles • 2-3 log kill is expected per cycle

18. Chemotherapy dosing • Clinical detection of cancer occurs when around 109 cells are present; lethal tumour burden is around 1012 cells • Once below the 109 threshold, we may not see cancer cells but, if they are there and not killed, they will regrow • It is essential to kill all cancer cells to achieve a cure

19. Clinical remission vs. actual cure Usually fatal 1012 Start chemo here 109 Clinical detection “remission” 106 Cells 103 CURE!!! 100 Time

20. Drug Resistance • Cancer cells have the ability to rapidly adapt to the stresses placed on them by the chemo • They find ways to circumvent the drug and become resistant • If not all cancer cells are killed quickly, remaining cells become resistant and more difficult to kill

21. Drug Resistance • Drug resistance is seen clinically as cancer progression while patients are being treated with drugs • Strategies can be tried to reverse resistance but they often are toxic and don’t work • Cyclosporine A, verapamil

22. Drug Resistance • DO NOT memorize specific resistance patterns for a particular drug • Understand, in general, how cancer cells may develop resistance • I will not ask you how a cancer becomes resistant to a particular drug (e.g. doxorubicin) but I may ask you how cancers resist chemotherapy in general

23. Drug interactions and the cell drug Influx transporter Apoptotic proteins Target (DNA) Efflux transporter Drug activator/deactivators

24. Drug ResistanceMechanisms • Decreased drug transport into cells • e.g. methotrexate • MTX has to be actively transported into the cell by folate transporters • Altering transport by altering the transporters (either qualitatively or quantitatively) results in lower drug concentration in the cell

25. Drug ResistanceMechanisms • Increased efflux of drug out of the cell • e.g. P-glycoprotein • Natural protein that transports toxins out of cells • Has a natural role in protecting cells from poisons • Overexpression leads to active efflux of chemo drugs from cancer cells • Usually naturally occurring compounds like etoposide, doxorubicin, microtubule agents • Drug can’t get into the cell in high enough concentrations for long enough to do anything

26. Drug ResistanceMechanisms • Impaired drug activation • e.g. Cytarabine (AraC) • Enzyme deoxycitidine kinase is required to convert cytarabine to its active form inside the cell • Lack of enzyme results in lower levels of active drug and clinical activity falls as a result

27. Drug ResistanceMechanisms • Accelerated inactivation of drug • e.g. cytarabine • Enzyme cytidine deaminase metabolizes active cytarabine to inactive form • Increased levels of this enzyme will inactivate the chemo • Cancer cell can upregulate the gene making this enzyme and the result is a resistant cell

28. Drug ResistanceMechanisms • Modification of cellular targets • e.g. Increased DHFR and methotrexate • Cell will have a target that the drug is aiming for • If you increase the number of potential targets, the chemo can only damage/inactivate so many of them • Multiple copies of critical RNA/proteins allow growth to continue

29. Drug ResistanceMechanisms • Impaired cell death pathways • Ineffective apoptotic pathways are probably the net result for resistance for many of the above mechanisms • This is a problem for virtually all chemotherapeutic drugs

30. Drug ResistancePrevention • Treating resistance is very difficult • Try not to let it happen by killing all the cells as rapidly as possible • Multi-agent combinations to kill cells by different mechanisms of action • Treat cancer when there are the fewest number of cells (principle of adjuvant chemotherapy) • Less chance for resistance • Fewer cells to kill to get that cure

31. Hormone Therapy • 20% of male cancers (prostate ca) and 40% of female cancers (breast, endometrial) are hormonally sensitive • Depriving cancer cells of a necessary growth factor causes tumour regression • Can be used in adjuvant setting to improve cure rates

32. Hormone Therapy • Hormone therapies work more slowly than chemotherapy • Unsuitable when a patient has massive life-threatening disease • Massive lung mets, liver mets • More suited for indolent disease in non life-threatening sites • Bone, lymph nodes in breast cancer • Since slower to respond, a minimum of 3 months of treatment is needed prior to assessing for response

33. Hormonal Interventions hypothalamus pituitary end organ (i.e. gonads) hormone receptor hormone (i.e. androgen or estrogen) aka food! cancer cell

34. Hormone TherapyTreatment Strategies • Remove the hormone producing gland • e.g. orchiectomy, oophorectomy • Interfere with hypothalamic – pituitary – end organ pathways • LHRH analogs • Decreased amount of necessary growth factor should result in regression of the tumour

35. Hormone TherapyTreatment Strategies • Block hormone synthesis at end organ • e.g. ketoconazole • This agent stops steroid synthesis in the adrenal gland • Has been used in breast cancer to stop adrenal sex steroid production • Many side effects as you can imagine as the patient has no normal adrenal steroids either

36. Hormone TherapyTreatment Strategies • Block the end organ hormone receptor • e.g. tamoxifen, flutamide • If you can’t manipulate the amount of hormone, block its receptor so it can’t stimulate the end organ • Tamoxifen for breast cancer; bicalutamide for prostate cancer • Cancer cell can’t bind its growth hormone

37. Hormonal TherapyAdministration • Slow onset of action • Not nearly so much toxicity to normal tissues • These agents need to be used continuously, as opposed to cyclical pulses of chemotherapy • Oral tablets; long acting im/sc depot preparations

38. Hormonal TherapyHormone Receptor Assays • Some cancers express hormone receptors on their surface • Some tumours can be checked in the lab for expression level • e.g. breast cancer and estrogen and progesterone receptors • This may help to predict who will respond to a hormonal manipulation

39. A word about adjuvant therapy…. • Patients being offered adjuvant therapy may have micrometastatic disease • you can’t see it on a scan • how do you know if the patient is benefiting? • Best given early post surgery or radiation so you are treating the least number of cancer cells • Have to discuss the potential benefits of treatment • no guarantees • based on population statistics

40. Adjuvant TherapyExample • A patient has stage II breast cancer • stats say that 60% of women will be cured with surgery • combination chemotherapy can improve the chances of survival by 25% (relative risk reduction of death) • Questions • Does that mean that every woman benefits from chemo? • Does that mean with chemo the cure rate rises to 85% (60 + 25 = 85)?

41. Example • 25% RRR means that the number of patients at risk is reduced relatively by 25% • 60% will be cured by surgery, therefore, • 40% of women at risk of dying with surgery only • reduce this by 25% (0.4 x 0.25=0.10) • 10% Absolute reduction in death

42. Surgery Alone 60% cured 40% will die You have no idea up front who is cured and who will die Surgery + Chemo 70% cured chemo adds 10% 30% will die You have no idea up front who is cured, who will die and who were the 10% that benefited Adjuvant Example

43. Adjuvant Chemo • Bottom line is that we know statistically for the population there is a benefit to treat • You never know which individual is going to benefit • you have to treat them all to give them the insurance policy • molecular profiling may help in the future

44. Adjuvant Chemo • Patients at the highest risk will derive the most potential benefit • Chemotherapy reduces death by 25% RRR • Stage I colon cancer • cure goes from 90% up to 92.5% • Stage III colon cancer • cure goes from 60% up to 70% • We don’t offer chemo to all if the potential benefit doesn’t outweigh the risks

45. Take Home Points • Chemotherapy works by exploiting biologic differences between cancer and normal cells; there is overlap and that causes toxicity • Chemotherapy kills rapidly dividing cells by interfering with normal biologic functions; non-viable cells can’t divide • Chemotherapy is given cyclically to give time for normal tissues to recover

46. Take Home Points • Hormone manipulations work more slowly, tend to be less toxic and can be very effective • Drug resistance is a big problem for both chemotherapy and hormonal therapy • Strategies to combine multiple chemotherapy drugs and hormone therapy may help to circumvent resistance

47. Self-Assessment Question #1 • Cancers may become resistant to chemotherapy by which ONE of the following? A) decreasing the amount of efflux transporters B) increasing the amount of influx transporters • increasing production of intracellular chemotherapy target proteins D) increasing pro-apoptotic proteins E) decreasing levels of drug deactivation enzymes

48. Self-Assessment Question #2 • Mary Jones has Stage III colon cancer. She has been offered adjuvant chemotherapy but when her sister had Stage I colon cancer 3 years ago she was told she didn’t need chemo. Which of the following is correct? • Adjuvant chemotherapy improves cure rates by killing microscopic cells B) Adjuvant chemotherapy improves cure rates by eradicating gross metastatic disease C) All patients who take adjuvant chemotherapy will benefit D) adjuvant chemotherapy has the same absolute improvement in survival irrespective of the stage of disease E) It doesn’t matter when you take adjuvant chemo, so Mary’s sister should go back to her oncologist for treatment