1. Management of locally advanced & metastatic prostate cancer Dr. Purvish. M. Parikh MD, DNB, PhD, FICP Professor & Head Department of Medical Oncology Tata Memorial Hospital

2. Prostate cancer Epidemiology Most commonly diagnosed cancer in men after 50 Life time risk -30% (microscopic) Risk of developing clinical disease -10% Incidence : 36% of all cancers in males -316000 new cases diagnosed -Mortality : 40000 deaths # Incidence : 4.8 / 100000 pop / year (Chennai) 8.1 / 100000 pop / year (Mumbai) 32000 new cases in 1999 # 1% increase in incidence every year

6. Natural history

7. Locally advanced prostate cancer

8. Locally advanced prostate cancer Clinical staging C2T4Tumor fixed or invades adjacent structures C2T3bSeminal vesicle invasion C1T3aExtracapsular extension (UL/BL) AUA stage AJCC 1997 Clinical disease

9. Natural history of clinical T3 prostate cancer Prostate cancer is inherently biologically heterogenous Patients have been staged differently in various studies StageN15 year PFS15 year DSS %95% CI% T1-T23004837.3-58.780.973.6-88.2 T3-T418346.632.7-60.556.544.6-68.4 M+1596.20.8-10.65.7-0.1-11.5 Johansson et al, JAMA,1997;227:467-471

10. Management options & Patterns of care Radical prostatectomy – 15.8% External beam radiotherapy – 34.3% Cryosurgery Combined modality treatments - 14.3% –Radical prostatectomy + ADT –External beam radiotherapy + ADT Systemic therapy –Hormonal therapy – 20.2% –Chemotherapy No cancer treatment – 15.5% Jones et al J Am Coll Surg,1995;180:545-554

11. Results of RP in T3 tumors StudyNMean FU (yrs) Pathologic stageOutcome Zincke 1986 1014.9C-49,D1-52LOR-17% Bosch, 1987 483.6C-25,D1-23LOR-30% Ouden, 1994 1003.6T3-39, T4-2,D1-48pT3-38% LOR, 31 % BF Lerner, 1995 8124.5T2c-17,T3-49, D1-33 DSS@15 yr-69% RP alone is unlikely to cure most men with cT3 disease Upto 50 % patients are found to have pelvic lymph node metastases at staging lymphadenectomy RP may have a role in selected patients with low/intermediate grade tumors

12. Results of EBRT in T3 tumors EBRT is less morbid & provides good local control & OS benefit Outcomes different in Pre-PSA & PSA era EBRT alone is unlikely to eradicate most locally advanced prostate cancers StudyNLocal RFS (n)OS (n) 5101551015 Stanford,1993409766340683820 POC,1994216706560563223 MDACC, 1995551888175724727 MSKCC,19934127260-6542- Results of conventional EBRT in T3 prostate cancer

13. Locally Advanced Prostate Cancer Modifications in Radiation Therapy Increasing the relative integral dose –Conformal radiation therapy –Proton beam therapy –Brachytherapy + EBRT –Intensity modulated radiation therapy Decreasing the volume of tumour prior to RT –Hormonal therapy –chemo cytoreduction Radiobiologic optimization –A ltered fractionation – Use of radiosensitisers – Neutron beam therapy

14. Locally advanced prostate cancer Hormone + Irradiation StudyMedian FU (yrs) StageNRXLocal relapse (%) PFS (%)OS (%) RTOG 83- 07 7B2,C99MEG16-- 98DES21-- RTOG 85-314.5T3,N1477LHRHa165375 468None292071 RTOG 86-104.5T2C-T4226LHRHa+ F463663 230None711563 EORTC3.8T3-T4,G346LHRHa-8579 45None-48

16. RTOG 92-02 Hanks GE,J Clin Oncol. 2003 Nov 1;21(21):3972-8. Locally advanced prostate cancer (PC; T2c-4),PSA <150 ng/mL. N= 1554 goserelin and flutamide X 2 months 65-70Gy EBRT – Prostate, 44-50 Gy EBRT – Pelvic nodes goserelin and flutamide X 2 months No additional therapy (short-term [ST]AD-RT) 24 months of goserelin (LTAD-RT);

17. RTOG 92-02 The LTAD-RT arm showed significant improvement in all efficacy end points except overall survival (OS; 80.0% v 78.5% at 5 years, P =.73). Tumors with Gleason scores of 8 to 10, the LTAD-RT arm had significantly better OS (81.0% v 70.7%, P =.044). There was a small but significant increase in the frequency of late radiation grades 3, 4, and 5 gastrointestinal toxicity ascribed to the LTAD-RT arm (2.6% v 1.2% at 5 years, P =.037), CONCLUSION: The RTOG 92-02 trial supports the addition of LT adjuvant AD to STAD with RT for T2c-4 PC.

18. DFS Overall survival for patients with Gleason scores 8 to 10

19. Primary hormone therapy RP is often not done in patients with prostate cancer due to poor risk for surgery, patient's wish, or physician's recommendation. N =151 patients with T1b, T1c, T2a, T2b or T3a prostate cancer Group I received leuprorelin acetate depot, 3.75 mg monthly Group II received LH-RHa with chlormadinone acetate (100 mg/day). At 12 weeks of treatment, 49% of the patients in both groups had a CR. Of the patients showing a partial response (PR) after 12 weeks of treatment, 25% in Group I and 52% in Group II improved to CR 1 year later (p<0.05). Group II showed a longer progression-free survival (p <0.05). PFS rates –T2b- 62% (Group I) and 91% (Group II) –T3- 43% (Group I) and 73% (Group II) Early primary hormone therapy is a reasonable treatment option for localized or locally advanced prostate cancer patients if radical prostatectomy was not scheduled. Akaza H, Jpn J Clin Oncol. 2000 Mar;30(3):131-6.

20. Adjuvant flutamide treatment improves DFS but does not improve median-term overall survival after radical prostatectomy for locally advanced, lymph node-negative prostate cancer. (Wirth MP, Eur Urol. 2004 Mar;45(3):267-70; )

21. Management of hormone sensitive metastatic prostate cancer

22. Goals of treatment Prolonging survival Preventing or delaying symptoms due to disease progression Improving and maintaining QOL Reducing treatment related morbidity.

23. Treatment options Androgen Deprivation –Bilateral orchiectomy –LHRH analogues - Goserilin, Leoprolide etc., –Total androgen Blockade : e.g..,adding flutamide Experimental options –Intermittent androgen suppression Treatment of Local Symptoms –"Channel" TURP. –Prostatic Urethral stenting –External Beam Radiotherapy

24. Physiology of androgens Orchidectomy

25. Questions! What are the standard initial treatment options? Are antiandrogens as effective as other castration therapies? Is combined androgen blockade better than castration alone Is early androgen deprivation therapy better than deferred ADT? Is intermittent ADT better than continuous ADT?

26. What are the standard initial treatment options? Orchidectomy –Simple & cost effective –Quick palliation –Compliance not a problem –Nonreversible –Carries significant psychological burden –Risk-Surgical complications –Side effects-Vasoactive symptoms, weight gain, mood lability, gynecomastia, fatigue, loss of libido, cognitive changes, osteopenia, hypercholesterolemia LHRH analogues –Costly –Risk of tumor flare –Potentially reversible –Convenient –No psychological burden –Side effects-Vasoactive symptoms, weight gain, mood lability, gynecomastia, fatigue, loss of libido, cognitive changes, osteopenia, hypercholesterolemia Diethystilbesterol –Convenient oral route –Risk of thrombosis & cardiovascular complications, edema, dyspnea, cramps –Compliance –No psychological burden

27. Single-Therapy Androgen Suppression in Men with Advanced Prostate Cancer: A Systematic Review and Meta-Analysis 24 RCT involving 6600 patients, (1966 - 1998) Results –LHRHa are equivalent to orchiectomy (10 trials, n=1908, HR- 1.262, 95% CI, 0.915-1.386). –There was no difference in OS among the LHRH analogues Leuprolide (hazard ratio, 1.0994 [CI, 0.207 to 5.835]) Buserelin (hazard ratio, 1.1315 [CI, 0.533 to 2.404]) Goserelin (hazard ratio, 1.1172 [CI, 0.898 to 1.390]). –Nonsteroidal antiandrogens are associated with lower OS( 8 trials, 2717 patients, HR 1.2158 [CI, 0.988 to 1.496]). –Treatment withdrawals are less frequent with LHRHa (0% to 4%) than with nonsteroidal antiandrogens (4% to 10%). Seidenfield et al Annals of Intern Med 2000, 132; 7: 566-577

28. Conclusions: –Survival after therapy with an LHRH agonist was equivalent to that after orchiectomy. –No evidence shows a difference in effectiveness among the LHRH agonists. –Survival rates may be somewhat lower if a nonsteroidal antiandrogen is used as monotherapy.

29. Are antiandrogens as effective as other castration therapies? Antiandrogens –Nonsteroidal (Flutamide,Bicalutamide, Nilutamide) Side effects-Gynecomastia, breast pain, hepatotoxicity –Steroidal (Cyproterone acetate) Side effects-Hepatotoxicity, edema, weight gain Monotherapy with nonsteroidal antiandrogens has equivalent survival to orchidectomy but with less toxicity (Seidenfield et al. AIM, 2000) Steroidal aniandrogens have an inferior TTP as compared to LHRHa (Thorpe et al, Eur Uro,1996)

30. Combined androgen blockade consists of an antiandrogen drug plus castration. Is combined androgen blockade better than castration alone?

31. N=1387 patients (Orch + Flutamide group-700,Orch + Placebo group-687) Patients receiving flutamide had greater rates of diarrhea and anemia. There was no significant difference between the two groups in overall survival (P=0.14). HR for flutamide as compared with placebo was 0.91 (90 % CI- 0.81-1.01). Flutamide was not associated with enhanced benefit in patients with minimal disease. Conclusions The addition of flutamide to bilateral orchiectomy does not result in a clinically meaningful improvement in survival among patients with metastatic prostate cancer. Eisenberger et al, NEJM,1998,339;1036-1042

33. 20 trials (6,320 patients). The pooled OR for overall survival was –1.03 (95% CI:0.85 to 1.25) @ 1year –1.16 (95% CI:1.00 to 1.33), @ 2 years –1.29 (95% CI:1.11 to 1.50) @ 5 years OS was only significant at 5 years. PFS was improved only at 1 year follow-up (OR=1.38) Cancer-free survival was improved only at 5 years (OR=1.22). Adverse events occurred more frequently with CAB and resulted in drug withdrawal in 10%. Quality of life was better with orchiectomy alone Conclusion MAB produces a modest overall and cancer-specific survival at 5 years but is associated with increased adverse events and reduced quality of life. Metaanalysis of CAB-1 Schmitt B et al. Cochrane Reviews 1999, Issue 2.

34. Metaanalysis of CAB-2 Metaanalysis of individual patient data 27 RCT, n=8275 men (Metastatic-88%, Locally advanced-12% Results –5932 (72%) men died; 80% deaths attributed to prostate cancer. –5-year survival was 25·4% with MAB vs 23·6% with AS alone (2p=0·11). –The results for cyproterone appeared slightly unfavourable to MAB (5-year survival 15·4% MAB vs 18·1% AS alone; 2p=0·04) –The results for nilutamide and flutamide appeared slightly favourable (5-year survival 27·6% MAB vs 24·7% AS alone; 2p=0·005). –Non-prostate-cancer deaths accounted for some of the apparently adverse effects of cyproterone acetate. Conclusion –In advanced prostate cancer, addition of an antiandrogen to AS improved the 5-year survival by about 2% or 3% (range 0-5%. ) PCTC meta-analysis.Lancet 2000, 355; 9214:1491-1498

36. Conclusions-CAB The findings range from no benefit (17 studies) to an estimated 3.7-7 months’ survival improvement(3 studies) In metaanalysis, CAB offers a stattistically significant but clinically questionable improvement in survival over orchidectomy or LHRHa monotherapy Benefit of CAB is limited to patients taking only NSAAs Benefit of CAB is seen only after 5 years GI (diarrhea, pain) & ophthalmologic side effects are more with CAB CAB results in 1 million $ per quality adjusted life year over orchidectomy alone

37. Early versus Late ADT 4 trials (n=2,167) –All trials were conducted prior to use of PSA testing & were heterogenous –All studies found PFS was consistently better in the early intervention group at all time points. Wilt T, et al Cochrane Reviews 2001, Issue 4. Overall Survival (%) 1 yr2 yr5 yr10 yr Early ADT 88734418 Deferred ADT 86713712 OR 1.16 95% CI: 0.90 to 1.49 1.08 95% CI: 0.89 to 1.33 1.19 95% CI: 0.95 to 1.50 1.50 95% CI: 1.04 to 2.16

38. OS PFS

39. Early versus Late ADT Wilt T, et al Cochrane Reviews 2001, Issue 4. The pooled estimate for the difference in OS survival favored early ADT but was significant only at 10 yrs The pooled estimate of prostate cancer specific survival at 2, 5, and 10 years favored early therapy but were not statistically different. The risk differences at 2, 5, and 10 years were 2.7%, 5.8%, and 4.6%.

40. Timing of ADT Conclusions The evidence from RCTs is limited by the –variability in study design, –stage of cancer and –subjects enrolled, –interventions utilized, –definitions and reporting of outcomes and –Lack of PSA testing for diagnosis & monitoring Additional studies are required to evaluate more definitively the efficacy and adverse effects of early ADT In particular trials should evaluate the impact of early ADT in patients with rising PSA syndrome

41. Timing of ADT Conclusions Early ADT offers a statistically significant benefit in PFS & OS Early ADT reduces disease progression and complications due to progression. There was no statistically significant difference in prostate cancer specific survival Early ADT leads to higher costs Treatment is most cost effective when started after the onset of symptoms Complications due to disease progression are more frequent in the deferred treatment group. Adverse events due to treatment are more frequent in the early treatment group.

42. Is intermittent ADT better than continuous ADT? Rationale –Prolonged ADT may cause androgen independence –Side effects are lesser with intermittent ADT No prospective randomized trials No guidelines for starting & stopping therapy No data available on testosterone levels, QOL, BMD & sexual function Two phase III studies are underway

43. Management of Hormone Refractory Prostate Cancer

44. Hormone refractory prostate carcinoma Definition: Disease progression despite castrate serum levels of testosterone Progression’ is defined by: –Increase in size of measurable lesions –Appearance of new measurable lesions – Increase in PSA >50% on at least 2 consecutive measurements –Increase in pain associated with new bony lesions Duration of response –Limited or no metastases-5 years –Metastatic disease-2 years Median survival approximately 1 year

46. Considerations in the management of HRPC Is the patients functionally castrated? What are the previous therapies? What was the response to previous therapy? What was the duration of response What is the current pace of the disease? Is the disease localized or metastatic at recurrence? Is the patient symptomatic? What are the sites & number of metastasis? Is there a risk of Pathologic # or cord compression? What are the comorbidities? Is the organ function compromised?

47. Management Options in HRPC Observation Withdrawl therapies Second line hormonal agents Estrogenic compounds-DES, Fosfetrol Antiandrogens-Bicalutamide, Flutamide, Nilutamide Adrenal suppressants-Ketoconazole, Aminoglutethimide Glucocorticoids-Prednisone, Dexamethasone, Hydrocortisone Chemotherapy For skeletal metastases –Bisphosphonates –External beam radiotherapy –Bone seeking radiopharmaceuticals-Sumarium 153, Strontium 89 Adjunctive therapies –Pain management –Radiofrequency ablation –Cryotherapy Investigational therapies

48. Antiandrogen withdrawl Preferred for patients who are using antiandrogens or CAB Withdrawl responses can be seen with –Nonsteroidal antiandrogens –Diethylstilbesterol –Megestrol acetate –Estramustine –Ketoconazole R esponse rates ~20% –Decline in PSA level –Occassional radiographic responses Expected timing of response –Flutamide-4 weeks (Half life of 6 hours) –Bicalutamide-8 weeks (Half life of 6 days) Response duration 4-6 months Continuation of LHRHa indefinitely despite relapse may be beneficial

49. Second line hormonal agents For patients who have received monotherapy (LHRHa/orchidectomy), addition of an antiandrogen is useful. Patients may respond differentially to different antiandrogens No major symtomatic relief More beneficial in –asymptomatic patients –biochemical failures Effects are short lived –median duration of response- 2-6 months Combining second line agents with AA does not confer any benefit & therefore should be used sequentially

50. Role of chemotherapy

51. Role of chemotherapy in HRPC Until 1990, chemotherapy was considered to have no role in the management of HRPC Active agents –Taxanes-Docetaxel, Paclitaxel –Mitoxantone –Estramustine –Adriamycin –Vinorelbine –Carboplatin Mitoxantrone is FDA approved for use in HRPC for palliation. It does not confer a survival benefit

52. Chemotherapy regimens in HRPC ChemotherapyPSA response (%) Measurable Response (%) Mitoxantrone+ Steroids33- Estramustine + Vinblastine31-5414-43 Estramustine + Taxane62-6543-57 Estramustine + etoposide +/- platinum5250-61 Estramustine + etoposide + paclitaxel5340 Doxorubicin + ketoconazle5558 Doxorubicin + ketoconazle/ vinblastine + estramustine 6775

53. Role of Docetaxel Petrylak et al NEJM, 351:15:1513-1520 P=0.02 P<0.001 P=0.30 Grade 3 or 4 neutropenic fevers, nausea and vomiting, and cardiovascular events were more common among patients receiving docetaxel and estramustine.

55. Role of Docetaxel-2 Tannock et al NEJM, 351:15:1502-1513 P<0.001 P=0.01 P=0.005

56. Tannock et al NEJM, 351:15:1502-1513

58. Conclusions Goal of chemotherapy for hormone refractory prostate cancer mainly to relieve symptoms Modest survival advantages have now been shown with some regiments

59. Bisphosphonates Incidence of bone metastases: 65%–75% Classification: osteolytic, osteoblastic, or combination/mixed Etiology: activation of osteoclasts and osteoblasts by soluble mediators released by prostate tumor cells metastasized to bone Treatment with a LHRHa decreases BMD and increases the risk of fracture in men with prostate cancer. Pamidronate has been shown to prevent bone loss in this group of patients. Smith et al NEJM, 2001,345:13:948-955

60. Rationale for using bisphosphonates Preferentially bind to bone surfaces undergoing active remodeling Inhibit osteoclast maturation and suppress osteoclast function Inhibit osteoclast recruitment to site of bone resorption Reduce bone-resorbing cytokine production Inhibit tumor-cell invasion and adhesion to bone matrix Induce apoptosis in tumor-cell lines May inhibit tumor-cell secretion of growth factors that stimulate osteoblasts Inhibit number and activity of osteoblasts

61. Role of bisphosphonates Randomized, double-blind placebo-controlled trial Randomization to –Intravenous Zolendronic acid 4 mg (n=214) –Intravenous Zolendronic acid 8 mg (n=221) –Placebo (n=208) Saad et al, JNCI,2002;94:1458-1468 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 All patients P=.021 Proportion of patients ZOMETA ® (zoledronic acid) 4 mg Placebo

62. 10 0 90 80 70 60 50 40 30 20 10 0 0 50 100150200 250 300350400 450500550 Percent of patients without event Time after start of therapy (days) N.R. = not reached P=.011 Median Time: ZOMETA ® (zoledronic acid) 4 mg = N.R. Placebo = 321 days Saad et al, JNCI,2002;94:1458-1468 Time to first skeletal-related event (SRE)

63. 0 0.4 0.8 1.2 1.6 2 2.4 2.8 Mean rate All patients P=.006 ZOMETA ® (zoledronic acid) 4 mg Placebo Time after start of therapy (days) N.R. = not reached 100 90 80 70 60 50 40 30 20 10 0 Percent of patients without event 25% Quartile Time: ZOMETA ® (zoledronic acid) 4 mg = N.R. Placebo = 321 days P=.011 055050045040035030025020015010050 Skeletal morbidity rate Saad et al, JNCI,2002;94:1458-1468

64. Time on study (months) Mean change from baseline 1 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 3691215 ZOMETA ® (zoledronic acid) 4 mg Placebo P=.03 P=.003 Change in composite pain score Saad et al, JNCI,2002;94:1458-1468

65. Palliative measures External beam RT (Local/Hemibody irradiation) –Painful bony metastases, –Spinal cord/nerve root compression Radio isotopes (Strontium-89 and Sumarium-153, Rhenium-188) –  -emitting isotopes which can improve bone pain –Administered as a single dose –Response rate –35-89% –Duration of response-3-12 months –Flare can occur in upto 23% of patients –More effective in combination with EBRT(Porter etal, IJROBP,1993) Anticholinergics Limited TURP for obstruction Radiofrequency ablation Cryosurgery Chemoembolization

66. Newer agents Satraplatin PC-SPECS Panzem (2-methoxyestradiol) Calcitriol Tyrosine kinase inhibitors –Imatinib, –Gefitinib Thalidomide Bortezomib VEGF inhibition- –Bevacizumab, –SU-5416 Flavopiridol GM-CSF Exisulind Trastuzumab Epothilone B analog –BMS-247550 Somatostatin Analogue –sms-D70 Rhenium-188 Endothelin-A Receptor Blockade –Atrasentan Antisense Oligonucleotides –ISIS 3521 –ISIS 5132 Gene therapy