Management of Hormone Refractory Prostate Cancer

Hormone refractory prostate carcinoma

• Definition: Disease progression despite castrate serum levels of testosterone 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

• Median survival approximately 1 year

Considerations in the management of HRPC • Is the patients functionally castrated? castrated? • What are the previous therapies? • What was the response to previous therapy? 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? symptomatic? • What are the sites & number of metastasis? • Is there a risk of Pathologic or cord compression? compression? • What are the comorbidities comorbidities?? • Is the organ function compromised?

Management Options in HRPC • • •

Observation Withdrawl therapies Second line hormonal agents • • • •

• •

Chemotherapy For skeletal metastases – – –

•

Bisphosphonates External beam radiotherapy Bone seeking radiopharmaceuticalsradiopharmaceuticals-Sumarium 153, Strontium 89

Adjunctive therapies – – –

•

Estrogenic compoundscompounds-DES, Fosfetrol Antiandrogens--Bicalutamide Antiandrogens Bicalutamide,, Flutamide Flutamide,, Nilutamide Adrenal suppressantssuppressants-Ketoconazole Ketoconazole,, Aminoglutethimide Glucocorticoids--Prednisone, Dexamethasone, Hydrocortisone Glucocorticoids

Pain management Radiofrequency ablation Cryotherapy

Investigational therapies

Antiandrogen withdrawl • Preferred for patients who are using antiandrogens • Withdrawl responses can be seen with – Nonsteroidal antiandrogens – Diethy lstilbesterol – Megestrol acetate – Estramustine – Ketoconazole

• Response rates ~20% –

Decline in PSA level

–

Occassional radiographic responses

• Expected timing of response –

Flutamide--4 weeks (Half life of 6 hours) Flutamide

–

Bicalutamide--8 weeks (Half life of 6 days) Bicalutamide

• Response duration 44-6 months

• Continuation of LHRHa indefinitely despite relapse may be beneficial

Second line hormonal agents • For patients who have received monotherapy (LHRHa/orchidectomy (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 responseresponse- 2 -6 months

• Combining second line agents with AA does not confer any benefit & therefore should be used sequentially

Role of chemotherapy

Role of chemotherapy in HRPC • Until 1990, chemotherapy was considered to have no role in the management of HRPC

• Active agents – Taxanes 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

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

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

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

• Inhibit number and activity of osteoblasts

Palliative measures • External beam RT (Local/Hemibody (Local/Hemibody irradiation) – Painful bony metastases, – Spinal cord/nerve root compression

• Radio isotopes (Strontium(Strontium-89 and SumariumSumarium-153, RheniumRhenium-188) – β -emitting isotopes which can improve bone pain – Administered as a single dose – Response rate –35 35--89% – Duration of responseresponse-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

Newer agents • • • • •

Satraplatin PC--SPECS PC Panzem (2 (2--methoxyestradiol) Calcitriol Tyrosine kinase inhibitors – Imatinib, – Gefitinib

• Thalidomide • Bortezomib • VEGF inhibitioninhibition– Bevacizumab Bevacizumab,, – SU SU--5416

• Flavopiridol • GM GM--CSF

• Exisulind • Trastuzumab • Epothilone B analog – BMS BMS--247550

• Somatostatin Analogue – sms sms--D70

• RheniumRhenium-188 • Endothelin Endothelin--A Receptor Blockade – Atrasentan

• Antisense Oligonucleotides – ISIS 3521 – ISIS 5132

• Gene therapy