Hormone therapy in prostate cancer 1

Hormone therapy in prostate cancer 1

1. Hormone therapy in prostate cancer Dr Deepika Malik Resident Radiotherapy

2. World wide burden. Prostate cancer fourth most common cancer in the world. second most common cancer in men. Incidence rates are highest in Australia/New Zealand and Northern America (ASR 111.6 and 97.2 per 100,000, respectively )but remain low in Asian populations with estimated rates of 10.5 and 4.5 in Eastern and South-Central Asia. With an estimated 307,000 deaths in 2012, prostate cancer is the fifth leading cause of death from cancer in men (6.6% of the total men deaths.)

3. Indian figures. Prostate cancer second most common cancer among males in large Indian cities like Delhi, Kolkatta , Pune and Thiruvananthapuram Third leading site of cancer in cities like Bangalore and Mumbai Among the top ten leading sites of cancers in the rest of the population based cancer registries (PBCRs) of India.

4. Prostate -male sex accessory gland that surrounds the urethra and contributes secretions to the ejaculate.

5. Testosterone production is regulated by luteinizing hormone (LH) and luteinizing hormone-releasing hormone (LHRH). The hypothalamus releases LHRH , which stimulates the release of LH from the pituitary gland. LH acts on specific cells in the testes to produce the majority of testosterone in the body. Most of the remaining androgens are produced by the adrenal glands.

6. The prostate requires androgenic hormones and an intact androgen receptor for normal growth and development. The major circulating androgenic hormone is Testosterone , 5α-reductase Testosterone 5α-dihydrotestosterone (DHT) inside the prostatic stroma

7. Dihydrotestosterone is a more potent androgen than testosterone binds to intracellular androgen receptor and activates the expression of selected target genes. Which then bring about a response -stimulation of cell division - inhibition of apoptosis - cellular differentiation.

8. Androgens , especially DHT promote the growth of both normal and cancerous prostate cells. This forms the basis of hormone therapy a.k.a androgen suppression or androgen deprivation therapy.

9. When to give hormonal therapy in prostate cancer? The NCCN Guidelines incorporate a risk stratification scheme that uses a minimum of stage, grade, and PSA to assign patients to risk groups. Risk groups are used to select the appropriate treatment options.

10. Gland architecture is examined Rated from 1 to 5 2 different specimens examined. Score for each added.

11. Prostate Specific Antigen Normally present in blood of healthy men at very low levels ( < 4 ng /ml) Glycoprotein enzyme, which liquifies semen and allows sperms to swim freely in semen. Raised in prostate cancer Nonspecific- also raised in BPH, prostatitis

12. Very Low : • T1c • Gleason score  6 • PSA <10 ng / mL • Fewer than 3 prostate biopsy cores positive  50% cancer in any core • PSA density <0.15 ng / mL /g Low: • T1-T2a • Gleason score  6 • PSA <10 ng / mL HORMONAL THERAPY NOT INDICATED

13. Intermediate: • T2b-T2c or • Gleason score 7 or • PSA 10-20 ng / mL High: • T3a or • Gleason score 8-10 or • PSA >20 ng / mL neoadjuvant 2 month concurrent +/- adjuvant 2 month - neoadjuvant 2 month concurrent adjuvant 24-36 months Very High: • T3b-T4 • Primary Gleason pattern 5

14. Metastatic ADT is the gold standard for patients Who present with metastasis at presentation.

15. Hormone therapy in prostate cancer As primary systemic therapy in metastatic prostate cancer Neoadjuvant / concomittant / adjuvant in combination with radiation for localised or locally advanced prostate cancer.

16. Duration of neoadjuvant ADT 3 trials The Canadian Urologic Oncology Group (CUOG) study - randomized 361 patients to either 3 or 8 months of neoadjuvant AST plus radiotherapy . - no difference in 5-year overall survival or freedom from failure -positive biopsies extracted 24 to 30 months after radiotherapy, were also not significantly different (14% vs. 9%, respectively; p = 0.34).

17. the Trans-Tasman Radiation Oncology group,TROG 96.01 -three-arm study with a radiotherapy-alone control group . -The other two arms were 3 and 6 months of neoadjuvant AST. -An improvement in local control and biochemical disease-free survival was seen in both AST arms (52% to 56%) over the control arm (38%; p <0.005), although the benefit seemed to be more pronounced in the 6-month arm . -Prostate cancer “ specific mortality was slightly less in the 6-month” (6%) but not the 3-month arm (8%) as compared to the control arm (9%).

18. Irish Clinical Oncology Research Group, - compared 4 to 8 months of Neoadj ADT with EBRT - no significant difference in overall survival or biochemical control.

19. The largest study, TROG 96.01 showed advantage to longer duration Neoadj AST Other 2 trials did not show any difference RTOG – 9910 , compared 8 and 28 weeks of neoadj AST. - over 1500 patients accrued - results are eagerly anticipated - until then available evidence remains conflicted.

20. Duration of Adjuvant Hormonal Therapy the Quebec L-101 trial randomized 161 intermediate-risk patients into 3 arms - radiotherapy alone, - 3-months of neoadjuvant AST and radiotherapy - -10 -months of neoadjuvant , concurrent, and adjuvant AST with radiotherapy Although the two experimental arms had superior 7-year PSA control rates over the control arm, there was no difference between the two AST arms (69% vs. 66%; p = 0.6;).

21. Laverdiere's L-200 study , subsequent confirmatory trial -296 intermediate-risk patients were randomized to either of the two experimental arms of L-101. -After a median follow-up of 3.7 years, the 5-year biochemical control was identical in both arms at 70%

22. for intermediate-risk patients , short-term AST (3 to 4 months of neoadjuvant and concurrent) appears to be sufficient, for high-risk patients , the addition of long-term (>2 years) adjuvant AST appears to confer improved outcomes.

23. History- The scientist Charles Huggins first established this over 75 years ago in work that led to his winning the Nobel Prize Huggins found that Bilateral orchiectomy could slow the growth of the disease

24. modalities Surgical castration Medical castration LHRH agonists LHRH antagonists Antiandrogens Androgen synthesis inhibitors Estrogens

25. Surgical castration The surgical removal of the testicles was the earliest form of hormone therapy for prostate cancer In 1941, Huggins and Hodges first treated men with prostate cancer with either orchiectomy (or estrogen ). They monitored changes in prostate size and observed that improvements in acid and alkaline phosphatases were associated with cancer-related symptom relief.

26. Bilateral orchidectomy rapidly reduces circulating androgens to castrate levels ( < 50 ng /dl) Limitations— -many patients find it psychologically unacceptable -some are not surgical candidates owing to advanced age.

27. Orchidectomy is preferred initial treatment in patients with impending spinal cord compression or ureteral obstruction.

28. LHRH Agonists (analogs) synthetic proteins  structurally similar to LHRH and bind to the LHRH receptor in the pituitary gland  (Intermittent pulsed LHRH ---- sustained FSH, LH release) High dose and continuous I/V LHRH agonist, inhibits gonadotrophin release due to receptor down regulation.

29. leuprolide Leuprolide acetate- Leuprolide depot- - leuprolide acetate in coated pellets; coating - dissolves at slow rate to allow sustained levels - intramuscularly - 7.5 mg every 28 days - 22.5 mg every 12 weeks - 30 mg every 16 weeks Leuprolide mini osmotic pump- delivers 120 microgm daily for 12months.

30. Goserelin implant 3.6 mg every 28 days 10.8 mg every 12 weeks Triptorelin depot 3.75 mg every 28 days 11.25 mg every 84 days.

31. Tumor flare most common side effect of LHRH agonists Disease flare up during the first week of therapy Hot flashes, erectile impotence, decreased libido, injection site reactions Caused by initial induction of FSH and LH by LHRH agonists –--- inreased testosterone production Manifests as exacerbation of disesase related symptoms, esp bone pains and urinary symptoms Resloves after 2 weeks To tackle this : antiandroen is initiated before administration of LHRH agonist and continued for 2-3 weeks

32. LHRH Antagonists Bind irreversibly to LHRH recerptors in pituitary , thus reducing testosterone to castrate levels. Major advantage over LHRH agonists–-- castrate levels of testosterone reached within 7 days ( compared to 28 days with antagonists) ; ---- no tumor flare and no need for antiandrogens .

33. Degerelix recently approved by FDA for advanced prostate cancer Available as 40 mg/ml and 20 mg/ml vials for subcutaneous injections Starting dose – 240 mg , followed by 80 mg every 28 days

34. estrogen  Although estrogens are also able to inhibit androgen production by the testicles, they are seldom used today in the treatment of prostate cancer because of their side effects.

35. Antiandrogens . Bind to androgen receptor in prostate cells – inhibit androgen uptake by prostate cancer cells ----- growth of cancer cells is retarded  they are used in combination with orchiectomy or an LHRH agonist .

36. Flutamide 750 mg/day perorally in 3 divided doses ( 250 mg TDS) Bicalutamide 50 mg OD Nilutamide 300 mg OD for 1 month , then 150 mg OD

37. Adverse effects of antiandrogens - Gynecomastia , hot flashes, GI disturbances, liver function abnormalitites , breast tenderness

38. Androgen synthesis inhibitors Inhibit androgen synthesis in testes and adrenals block testosterone production by inhibiting an enzyme called CYP17. (produces testosterone from cholesterol). Three androgen synthesis inhibitors are approved in the United States. – ketoconazole , aminoglutathemide , abireterone acetate

39. Ketoconazole Imidazole antifungal 400 mg TDS orally a/e- GI intolerance, hypoadrenalism strong inhibitor of CYP A1 and CYP 3A4 , therfore contraindicated with midazolam , traizolam ( commonly used in prostate cancer patients) Absorption requires gastric acidity , so should not be given with H2 blockers, PPI’s

40. Toxicities of ADT Fatigue weight gain osteoporosis depression decreased cognitive function erectile dysfunction loss of libido Gynecomastia Anemia decreased high-density lipoprotein hot flashes

41. In a recent study of 50,613 men with prostate cancer compiled from a linked database of Surveillance Epidemiology and End Results (SEER) and Medicare, the addition of AST significantly increased the risk of any fracture from 12.6% to 19.4%; fractures requiring hospitalization similarly increased from 2.37% to 5.19%

42. chemoprevention 5 α reductase inhibitors have been shown to decrease risk of prostate cancer Inhibit 5α-reductase , such that testosterone does not convert to its more active form DHT Finesteride , Dutasteride American Society of clinical oncology and American Urological Association recommend that asymptomatic men with PSA less than 3 ng /ml may benefit . Risk of developing high grade prostate cancer

43. Take home message Hormone therapy is an integral part of managing prostate cancer For metastatic cases – hormone therapy is the Gold standard For early cases – hormone therapy is given as per risk stratification Chemoprevention- with risk of developing high grade prostate cancer.

44. Thank you.