Pocket Oncology (Pocket Notebook Series), 1st Ed.

RECURRENT/METASTATIC PROSTATE CANCER

Eric L. Smith

Biochemical Recurrence

• By PSA After Definitive RT

Dfn: Post RT rising PSA by 2 ng/mL or more above the nadir PSA

W/U options include: Eval for local/distant disease: Bone scan, CT/MRI/US, prostate bx

Candidate for salvage surgery if original T1–T2, NX or N0, life expectancy >10 y, current PSA <10

No distant mets identified, prostate bx pos, candidate for salvage as above

Local tx options: RP, cryosurgery, brachytherapy ± ADT

No distant mets identified, prostate bx neg, or not candidate for salvage

Observation vs. ADT (see below) Consider intermittent ADT

• By PSA After Definitive RP

Dfn: Undetectable PSA after RP w/subsequent detectable PSA >0.2 ng/ml that is confirmed on subsequent determination

W/U options include: bone scan, CT/MRI/US, bx prostate bed if suggested by imaging

No distant mets identified Observation vs. Salvage RT ± ADT vs. ADT alone, consider intermittent ADT

• Distant mets identified See below

Initial Treatment for Metastatic Castration Sensitive Disease

• Dfn: Prostate Ca that responds to lowering testosterone to castrate levels (conventionally defined as <50 ng/dl)

• N1 RT + long-term neoadj/concurrent/adj ADT (2–3 y) or ADT alone

• M1 ADT or dual ADT + anti-androgen

Androgen Deprivation Therapy

• GnRH agonists such as leuprolide as daily or depot inj ± anti-androgen such as bicalutamide for at least 7 d to prevent flare

• GnRH agonist + anti-androgen (eg, bicalutamide, nilandron)

• Degarelix (pure GnRH antagonist, thus avoiding initial disease flare)

• Rarely/historically: Orchiectomy

• S/e: Hot flashes, vasomotor instability, osteoporosis, fractures, obesity, diabetes, HLD, CAD, decreased libido, mood lability S/e increase w/duration of tx

Treatment for Castration Resistant Disease

• Dfn Progressive disease despite castrate levels of testosterone

• Maintain castrate levels of testosterone w/GnRH agonist

• 2nd hormone Rx: Anti-androgens as above, anti-androgen withdrawal, abiraterone, ketoconazole

Treatment for Castration Resistant Disease Continued

• Docetaxel Taxane (NEJM 2004;351:1502; JCO 2008;26:242)

• Sipuleucel-T DC leukapheresed & exposed to prostatic acid phosphatase Ag fused to GM-CSF ex vivo, & re-introduced; OS benefit but no change in PSA or tumor burden, appropriate only if asx, ECOG 0–1, no visceral mets, not on: Steroids, RT, chemo, or immunotx, & life expectancy >6 mos (NEJM 2010;363:411)

• Cabazitaxel Taxane derivative, only used post docetaxel (Lancet 2010;376:1147)

• Abiraterone Acetate Inhibits cytochrome P450 c17 (lyase, hydroxylase) reduces testosterone/dihydrotestosterone from adrenal, testis, & tumor sources, approved for pts both pre & post docetaxel (NEJM2010;364:1995; NEJM 2013; 368:138)

• Enzalutamide Inhibits nuclear translocation, DNA binding, & coactivator recruitment of/by androgen receptor, post docetaxel (NEJM 2012;367:1187)

Notes: Above are the only 5 systemic agents that have shown increased OS in this setting.

• Mitoxantrone for Pts who are not candidates for docetaxel

All agents above except enzalutamide & sipuleucel are given in combination w/prednisone.

Mechanism of Action of Anti-Androgen Therapies

Clinical Use Algorithm

• Castration-resistant mets before docetaxel

Maintain castrate levels of testosterone w/LHRH agonist

Further options include:

Abiraterone

Sipuleucel-T (if meets requirements above)

Docetaxel

Palliative RT

Bone-seeking radiopharmaceuticals

• POD Post-Docetaxel Rx

Maintain castrate levels of testosterone w/LHRH agonist

Further options include:

Abiraterone

Enzalutamide

Cabazitaxel

Docetaxel rechallenge if previously sensitive

Mitoxantrone

Sipuleucel-T (if meets requirements above)

• Special Consideration for Bone Mets

In addition to above:

Denosumab or Zoledronic acid to lower risk of SREs in castration-resistant disease

If symptomatic: Palliative RT or radionuclide (β emitters)

Small Cell

• Distant mets identified on imaging

Consider bx if suspect small cell

• Small cell pos on bx treat similar to SCLC

Cis/Etoposide

Carbo/Etoposide

Docetaxel-based regimens

Monitoring

• After N1 or M1 Physical exam & PSA q3mos,