LIIRII agonist medical castrations or surgical aie equivalent

Patients with T3b and T4 disease have a very high risk of recurrence and are not candidates for radical prostatectomy because of extensive local spread of the dis-

ease.

C Androgen ab/ation with a /uteinizing hormone-re/easing hormone (LHRH) agonist p/us an antiandrogen shou/d be used prior to radiation therapy for patients with /oca//y advanced prostate cancer to improve outcomes over radiation therapy a/one. Recent evidence suggests that androgen ablation should be instituted at diagnosis rather than waiting for symptomatic disease or progression to occur. In a randomized clinical trial enrolling 500 men with locally advanced prostate cancer, who were randomized to either immediate initiation of androgen ablation with either orchiectomy or androgen ablation, or deferred hormonal therapy, individuals with immediate ther apy had a median actuarial cause-specific survival duration of 7.5 years for immediate treatment and 5.8 years for deferred treatment.36

Patient Encounter 2: Initial Presentation and Treatment

FF is a 66-year-old male who presents to the clinic complaining of impotence for the last 1 to 2 months and requesting a prescription for Cialis. Upon questioning, he gives a history of fatigue, gradual weight loss of 10 lb, and difficulty with urination that began about 6 months ago.

Physical exam is positive for a 1-cm nodule in the prostate and his laboratories reveal the following: PSA 12 ng/dL (12 mcg/L); PSA from 1 year ago was 2 ng/dL (2 mcg/ L).

A prostate biopsy by transrectal ultrasound (TRUS) reveals adenocarcinoma of the prostate, with a Gleason score of 8. CT scanning and bone scan reveal disease that is metastatic to the bone, and a final stage of T4 (metastatic) prostate cancer is determined.

What is the pathophysiology underlying his clinical presentation? Based on his stage, what are treatment options for this patient?

Androgen ablation therapy, with either orchiectomy, an LHRH agonist alone or an LHRH agonist plus an antiandrogen (combined androgen blockade), can be used to provide palliation for patients with advanced (stage D2) prostate cancer. Estrogens were once widely used; however, the primary estrogen, diethylstilbestrol (DES), was withdrawn from the U.S. market in 1997 due to the increased cardiovascular risk. Secondary hormonal manipulations, cytotoxic chemotherapy, or supportive

care is used for the patient who progresses after initial therapy. Nonpharmacologic Therapy Expectant Management

Expectant management, also known as observation or watchful waiting, involves monitoring the course of disease and initiating treatment if the cancer progresses or the patient becomes symptomatic. A PSA and DRE are performed every 6 months with a repeat biopsy at any sign of disease progression. The advantages of expectant management are avoiding the adverse effects associated with definitive therapies such as radiation and radical prostatectomy and minimizing the risk of unnecessary therapies. The major disadvantage of expectant management is the risk that the cancer progresses and requires a more intensive therapy.

Orchiectomy

Bilateral orchiectomy, or removal of the testes, rapidly reduces circulating androgens to castrate levels (i.e., serum testosterone levels less than 50 ng/dL [1.74 nmol/L]).

However, many patients are not surgical candidates owing to their advanced age,

and other patients find this procedure psychologically unacceptable. Orchiectomy is the preferred initial treatment in patients with impending spinal cord compression or ureteral obstruction.

Radiation

The two commonly used methods for radiation therapy are external beam radiotherapy 33

and brachytherapy. In external beam radiotherapy, doses of 70 to 75 Gy are delivered in 35 to 41 fractions in patient with low grade prostate cancer and 75 to 80 Gy for those with intermediate or high-grade prostate cancer. Brachytherapy involves the permanent implantation of radioactive beads of 145 Gy 125-Iodine or 124 Gy of 103-Palladium and is generally reserved for individuals with low-risk cancers.

Radical Prostatectomy

Complications from radical prostatectomy include blood loss, stricture formation, incontinence, lymphocele, fistula formation, anesthetic risk, and impotence. Nerve-sparing radical prostatectomy can be performed in many patients; 50% to 80% regain sexual potency within the first year. Acute complications from radical prostatectomy and radiation therapy include cystitis, proctitis, hematuria, urinary retention, penoscrotal edema, and impotence (30% incidence).15 Chronic complications include

proctitis, diarrhea, cystitis, enteritis, impotence, urethral stricture, and incontinence. Since radiation and prostatectomy have significant and immediate mortality when compared with observation alone, many patients may elect to postpone therapy until symptoms develop.

Pharmacologic Therapy

LHRH Agonists

LHRH agonists are a reversible method of androgen ablation and are as effective as orchiectomy in treating prostate cancer38 (Table 92-7). Currently available LHRH

agonists include leuprolide, leuprolide depot, leuprolide implant, triptorelin depot, triptorelin implant, and goserelin acetate implant. Leuprolide acetate is administered once daily, whereas leuprolide depot and goserelin acetate implant can be administered either once monthly, once every 12 weeks, or once every 16 weeks (leuprolide depot, every 4 months). The leuprolide depot formulation contains leuprolide acetate in coated pellets. The dose is administered intramuscularly, and the coating dissolves at different rates to allow sustained leuprolide levels throughout the dosing interval. Goserelin acetate implant contains goserelin acetate dispersed in a plastic matrix of d,l-lactic and glycolic acid copolymer and is administered subcutaneously. Hydrolysis of the copolymer material provides continuous release of goserelin over the dosing period. A recently approved leuprolide implant is a mini-osmotic pump that delivers 120 mcg of leuprolide daily for 12 months. After 12 months, the implant is removed and a different implant can be placed. Triptorelin LA is administered as an intramuscular (IM) injection of 11.25 mg every 84 days. Triptorelin depot is administered 3.75 mg once every 28 days.

Table 92-7 LHRH Agonist

LHRH

Adverse Effects (Similar

Agonist

Usual Dose

for All Agents)

Leuprolide

7.5 mg every 28 days

Gynecomastia

depot

22.5 mg every 12

Hot flashes

weeks

Decreased libido.

30 mg every 16 weeks

impotence,

Fatigue

Goserelin

.16 mg every 28 days

Tumor flare In fiist 2 weeks

implant

10.S mg every

Osteopenia with long-term

12 weeks

use

iMptorciiri

3.75 mg every 28 days

depot

11.25 mg every 84 days

Several randomized trials have demonstrated that leuprolide, goserelin, and triptorelin are effective agents when used alone in patients with advanced prostate cancer.26 Response rates around 80% have been reported, with a lower incidence of adverse effects compared with estrogens. There are no direct comparative trials of the currently available LHRH agonists or the dosage formulations, but a recent metaanalysis reported that there is no difference in efficacy or toxicity between leuprolide and goserelin. Triptorelin is a more recent addition but is generally considered equally effective. Therefore, the choice between the three agents is usually made on the basis of cost and patient and physician preference for a dosing schedule.

The most common adverse effects reported with LHRH agonist therapy include a disease flare-up during the first week of therapy, hot flashes, erectile impotence, decreased libido, and injection-site reactions.26 The disease flare-up is caused by an initial induction of LH and FSH by the LHRH agonist, leading to an initial phase of increased testosterone production, and manifests clinically as either increased bone pain or increased urinary symptoms.26 This flare reaction usually resolves after 2 weeks and has a similar onset and duration pattern for the depot LHRH products.39,40 Initiating an antiandrogen prior to the administration of the LHRH agonist and continuing for 2 to 4 weeks is a frequently employed strategy to minimize this initial tumor flare.27

LHRH agonist monotherapy can be used as initial therapy, with response rates similar to orchiectomy. There is a lower incidence of cardiovascular-related adverse effects associated with LHRH therapy than with estrogen administration. Patients should be counseled to expect worsening symptoms during the first week of therapy, appropriate pain and symptom management is required during this period and a short course of concomitant antiandrogen therapy may need to be considered prior to initiating the LHRH agonist. Caution should be exercised if initiating LHRH agonist therapy in patients with widely metastatic disease involving the spinal cord or having the potential for ureteral obstruction because irreversible complications may occur.

Another potentially serious complication of androgen deprivation therapy is a resultant decrease in bone-mineral density, leading to an increased risk for osteoporosis, osteopenia, and an increased risk for skeletal fractures. Most clinicians recommend that men starting long-term androgen deprivation therapy should have a base-

line bone-mineral density and be initiated on a calcium and vitamin D supplement. Gonadotropin-Releasing Hormone (GnRH) Antagonists

An alternative to LHRH agonists is the recently approved GnRH antagonist, degralix. Degralix works by binding reversibly to GnRH receptors on cells in the pituitary gland, reducing the production of testosterone to castrate levels. The major advantage of degralix over LHRH agonists is the speed at which it can achieve the drop in testosterone levels; castrate levels are achieved in 7 days or less with degralix, compared to 28 days with leuprolide, eliminating the tumor flare seen and need for anti-androgens, with LHRH agonists.

In a trial of 610 men with advanced prostate cancer, degralix was shown to be equivalent to leuprolide in lowering testosterone levels for up to 1 year and is approved by the FDA for the treatment of advanced prostate cancer. Degralix is available as a 40 mg/mL and a 20 mg/mL vial for SC injection and the starting dose is 240 mg followed by 80 mg every 28 days. The starting dose should be split into two injections of 120 mg.

The most frequently reported adverse reactions were injection-site reactions, including pain (28%), erythema (17%), swelling (6%), induration (4%), and nodule (3%). Most were transient and mild to moderate, leading to discontinuation in less than 1% of study subjects. Other adverse effects included elevations in lever function tests, which occurred in approximately 10% of study subjects. Like other methods of androgen deprivation therapy, osteoporosis may develop and calcium and vitamin D supplementation should be considered.

Degralix has not been studied in combination with antiandrogens and routine use of the combination cannot be recommended.

Like degralix, abarelix is a GnRH antagonist, with the same advantage of reducing testosterone to castrate levels rapidly and avoiding the tumor flare associated with LHRH agonists. Unfortunately, abarelix is also associated with severe allergic reactions, including syncope and hypotension, which occur in approximately 1% of initial doses and an increased frequency with repeat doses, for an incidence approaching 5% overall. Therefore, abarelix is available only through a restricted distribution program (Plenaxis PLUS Program) and is only indicated for men with advanced prostate cancer who cannot tolerate LHRH agonist therapy and who refuse surgical castration, and have one or more of the following: (a) risk of neurologic compromise due to metastases; (b) ureteral or bladder outlet obstruction due to local encroachment or meta-static disease; or (c) severe bone pain from skeletal metastases persisting on narcotic analgesia. The recommended dose of abarelix is 100 mg administered intramuscularly to the buttock on days 1, 15, 29 (week 4), and every 4 weeks thereafter.

Table 92-8 Antiandrogens

A riti a ndrog en Us u a I Do se Adverse Effects

Flutamide

Hot flushes

Gl disturbances (diarrhea) Liver function test abnorma lities Breast tenderness Methemoglobinemia

Bicriluiaitiide

50 m^/day

Gynecomastia Hot flushes

Gl disturbances (diarrhea) Liver function test abnormalities Breast teEtderness

Nilutamide

300 mg/day for

Gynecomastia

first month

Hot Flushes

then 150

Gl disturbances (nausea or

rfig/day

constipation) Liver function test abnorma nties Breast tenderness Visual disturbances (impaired dark adaptation) Alcohol intolerance Interstitial pneumonitis

Antiandrogens

39 38

Three antiandrogens, flutamide, bicalutamide, and nilutamide, are currently available (Table 92-8). Cyproterone is another agent with antiandrogen activity but is not available in the United States. Antiandrogens have been used as monotherapy in previously untreated patients, but a recent metaanalysis determined that monother-apy with antiandrogens is less effective than LHRH agonist therapy.40 Therefore, for advanced prostate cancer, all currently available antiandrogens are indicated only in combination with androgen-ablation therapy; flutamide and bicalutamide are indicated in combination with an LHRH agonist; and nilutamide is indicated in combina-

tion with orchiectomy.

The most common antiandrogen-related adverse effects are listed in Table 92-7. In the only randomized comparison of bicalutamide plus an LHRH agonist versus flut-amide plus an LHRH agonist, diarrhea was more common in flutamide-treated patients. Antiandrogens can reduce the symptoms from the flare phenomenon associated

with LHRH agonist therapy. Combined Androgen Blockade

Although up to 80% of patients with advanced prostate cancer will respond to initial hormonal man2i2pulation, almost all patients will progress within 2 to 4 years after initiating therapy.2 Two mechanisms have been proposed to explain this tumor resistance. The tumor could be heterogeneously composed of cells that are hormone dependent and hormone independent, or the tumor could be stimulated by extratesticular androgens that are converted intracellularly to DHT. The rationale for combination hormonal therapy is to interfere with multiple hormonal pathways to completely eliminate androgen action. In clinical trials, combination hormonal therapy, sometimes also referred to as maximal androgen deprivation or total androgen blockade, or combined androgen blockade (CAB), has been used. The combination of LHRH agonists or orchiectomy with antiandrogens is the most extensively studied CAB approach.

Many studies comparing CAB with conventional medical or surgical castration have been performed. 1,41 2 In studies with LHRH agonists, the results have varied, with no consistent benefit demonstrated for CAB. A recently completed National Cancer Institute (NCI) intergroup trial involving 1,387 evaluable stage D2 prostate cancer patients failed to show any significant survival benefits for the combination of orchiectomy plus flutamide over orchiectomy alone.43 Like other studies of CAB, overall survival was longest in patients with minimal disease. Diarrhea, elevated liver function tests, and anemia were more common in those patients who received flutam-ide.

A metaanalysis of 27 randomized trials in 8,275 patients (4,803 treated with flutamide, 1,683 treated with nilutamide, and 1,784 treated with cyproterone) comparing

CAB with conventional medical or surgical castration showed a small survival benefit at 5 years for those treated with flutamide or nilutamide (27.6%) compared to those with castration alone (24.7%; P = 0.0005)41

In one of the few combination androgen-deprivation studies comparing two different antiandrogens (bicalutamide versus flutamide), the time to treatment failure (the main study end point), time to progression (as defined by appearance of new or worsening bone or extraskeletal lesions), and time to death were equivalent, suggesting that the two treatments are equally effective.44

Although some investigators now consider CAB to be the initial hormonal therapy of choice for newly diagnosed advanced prostate cancer patients, the clinician is left to weigh the costs of combined therapy against potential benefits in light of conflicting results in the randomized trials3 and the modest benefit seen in the metaanalysis.41 For those trials that did show an advantage for CAB, whether these effects are specific to the testosterone-deprivation method (orchiectomy vs leuprolide vs gos-erelin), the antiandrogen, the duration of therapy, or patient selection is not clear. Until further carefully designed studies that use survival, time to progression, quality of life, patient preference, and cost as end points are conducted, it is appropriate to use either LHRH agonist monotherapy or CAB as initial therapy for metastatic prostate cancer. CAB may be most beneficial for improving survival in patients with minimal disease and for preventing tumor flare, particularly in those with advanced metastatic disease. All other patients may be started on LHRH monotherapy, and an antiandrogen may be added after several months if androgen ablation is incomplete.

There is considerable debate concerning when to start hormonal-deprivation therapy in patients with advanced prostate cancer.26 The original recommendation to start therapy when symptoms appeared was based on the Veterans Administration Cooperative Urologic Research Group (VACURG) trials, in which no overall survival difference was demonstrated in patients who either started DES initially or crossed over to active treatment when4s4ymptoms appeared; the excess mortality was attributed to estrogen administration.4 Because LHRH agonists and antiandrogens are viable therapies with less cardiovascular toxicity, it is not clear whether delaying therapy is justified with these agents. Reanalysis of the original VACURG data45 and recent combined androgen-deprivation trials demonstrate a survival advantage for young, good-performance status, minimal-disease patients treated initially with hormonal therapy, suggesting that early intervention before symptoms appear may be appropriate.45 The issue of when best to start hormonal therapy is the subject of several ongoing clinical trials.45

Secondary Therapies

Secondary or salvage therapies for patients who progress after their initial therapy depend on what was used for initial management.3 For patients initially diagnosed with localized prostate cancer, radiotherapy can be used in the case of failed radical prostatectomy. Alternatively, androgen ablation can be used in patients who progress after either radiation therapy or radical prostatectomy.

In patients treated initially with one hormonal modality, secondary hormonal manipulations may be attempted. This may include adding an antiandrogen to a patient who incompletely suppresses testosterone secretion with an LHRH agonist. In patients that have progression while receiving CAB, withdrawing antiandrogens, or using agents that inhibit androgen synthesis may be attempted. Supportive care, chemotherapy, or local radiotherapy can be used in patients who have failed all forms of androgen-ablation manipulations because these patients are considered to have hormone-refractory prostate cancer.

For patients who initially received an LHRH agonist alone, castration testosterone levels should be documented. Patients with inadequate testosterone suppression (greater than 20 ng/dL, 0.7 nmol/L) can be treated by adding an anti-androgen or performing an orchiectomy. If castration testosterone levels have been achieved, the patient is considered to have androgen-independent disease, and palliative androgen-in-dependent salvage therapy can be used.

® Antiandrogen withdrawal, for patients having progressive disease while receiving combined hormonal blockade with an LHRH agonist plus an antiandrogen, can provide additional symptomatic relief. Mutations in the androgen receptor have been documented that cause antiandrogen compounds to act like receptor agonists.

If the patient initially received CAB with an LHRH agonist with an antiandrogen,

then androgen withdrawal is the first salvage manipulation. Objective and subjective responses have been noted following the discontinuation of flutamide, bicalutam-ide, or nilutamide in patients receiving these agents as part of combined androgen ablation with an LHRH agonist. Mutations in the androgen receptor have been demonstrated that allow antiandrogens such as flutamide, bicalutamide, and nilutamide (or their metabolites) to become agonists and activate the androgen receptor. Patient responses to androgen withdrawal manifest as significant PSA reductions and improved clinical symptoms. Androgen withdrawal responses lasting 3 to 14 months have been noted in up to 35% of patients, and predicting response seems to be most closely related to longer androgen exposure times.44 Incomplete cross-resistance has been noted in some patients who received bicalutamide after they had progressed while receiving flutamide, suggesting that patients who fail one antiandrogen may still respond to another agent. Adding an agent that blocks adrenal androgen synthesis, such as amino-glutethimide, at the time that androgens are withdrawn may produce a better response than androgen withdrawal alone. Because of the potential for response immediately after antiandrogen withdrawal, a sufficient observation and assessment period (usually 4-6 weeks) is usually required before a patient can be enrolled on a clinical trial evaluating a new agent or therapy for advanced prostate cancer.

Androgen synthesis inhibitors, such as aminoglutethimide 250 mg orally every 6 hours or ketoconazole 400 mg orally three times a day, can provide symptomatic relief for a short time in approximately 50% of patients with progressive disease des-

pite previous androgen-ablation therapy. Adverse effects during aminoglutethim-

ide therapy occur in approximately 50% of patients. CNS effects that include lethargy, ataxia, and dizziness are the major adverse reactions. A generalized morbilliform, pruritic rash has been reported in up to 30% of patients treated. The rash is usually self-limiting and resolves within 5 to 8 days with continued therapy. Adverse effects from ketoconazole include GI intolerance, transient rises in liver and renal function tests, and hypoadrenalism. Additionally, ketoconazole is a strong inhibitor of CYP1A2 and CYP3A4 and is contraindicated in combination with a number of medications that are commonly used in men with prostate cancer, including cisapride, lovastatin, midazolam, and triazolam because ketoconazole inhibits their metabolism and leads to increased toxicity. Arrhythmias often fatal have been reported with the combination of cisapride and ketoconazole. Absorption of ketoconazole requires gastric acidity; therefore, ketoconazole should not be administered with H2-blockers, proton pump inhibitors, or antacids. Additionally, ketoconazole should not be administered with strong CYP3A4 inducers, such as rifampin, as this may reduce the effectiveness of ketoconazole because it is also a substrate for CYP3A4. Ketoconazole is combined with replacement doses of hydrocortisone to prevent symptomatic hypoad-

renalism.

Table 92-9 First-Line Chemotherapy for Metastatic Hormone-Independent Prostate Cancer

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Advrrir Eflotli

Pph fldjmtnwns

Flukt neiMTiiori, ibpcciji >nui osilii, myelüsnifipmiisa hypciiensiliviljf

Eík.TTU. gyiWfljTHdi, IpLKOftffiií, ÍIiíWMmVJ Irlli 0( Ihr-ombüdmlxJt ewnli

Hspar*:

B AST/ALï il tjrcjHf lhan 15 K !he upp« lirnl of rmfnul jrïi jlkilnn' phoipharaw gie.im Hun 3.1 upp« limit ni rtOfmit do rwt «JnwhtCT

HírnflloftJ^jtc imuip-comptas btood couru recowipd HCmúMlagx.

I miiiPíLsnpirie hfevJ counr KYaw^pd

After all hormonal manipulations are exhausted, the patient is considered to have androgen-independent disease, also known as hormone-refractory prostate cancer. At this point, either chemotherapy or palliative supportive therapy is appropriate. Palliation can be achieved by pain management, using radioisotopes such as strontium-89 or samarium-153 lexidronam for bone-related pain, analgesics, corticosteroids, bi-sphosphonates, or local radiotherapy.33,45,46

Skeletal metastases from hematogenous spread are the most common sites of distant spread of prostate cancer. Typically, the bone lesions are osteoblastic or a combination of osteoblastic and osteolytic. Bisphosphonates may prevent skeletal related events and improve bone-mineral density. A randomized, controlled trial of zoled-ronic acid at a dose of 4 mg every 3 weeks reduced the incidence of skeletal-related

events by 25% (P = 0.021) compared to placebo. The usual dose of pamidronate is 90 mg every month and the usual dose of zoledronic acid is 4 mg every 3 to 4 weeks. A trial of pamidronate or zoledronic acid can be initiated in prostate cancer patients

with bone pain; if no benefit is observed, the drug may be discontinued.

Chemotherapy with docetaxel and prednisone improves survival in patients with hormone-refractory prostate cancer.

Docetaxel 75 mg/m every 3 weeks combined with prednisone 5 mg twice a day improve survival in hormone-refractory metastatic prostate cancer.49 The most common adverse events reported with this regimen are nausea, alopecia, and bone marrow suppression. In addition, fluid retention and peripheral neuropathy, known effects of docetaxel, are observed. Docetaxel is hepatically eliminated; patients with hepatic impairment may not be eligible for treatment with docetaxel because of an increased risk for toxicity.

Patient Encounter 3: Progressive Disease

AX is a 62-year-old male who was initially diagnosed with metastatic prostate cancer 5 years ago. He was initially started on leuprolide and has progressed through treatment as described in the treatment summary below.

Treatment Summary

Date

PSA

Intervention

9/2/04

25 rig/ml (25 mcg/L)

Started Jeuprolide 7,5 nng

IM q month

12/2/04

2 ng/mL (2 mcg/L)

Continued leu p rol ids

6/2/06

22 ng/mL (22 mcg/L)

Added bicalutamide 50

mg po daaiy

9/2/06

5 rig/mL (5 mcg/L)

Continued leu p rol ids and

bicalutarnide

10/2/07

32 ng/mL [32 mcg/U

Continued leuprollde,

stopped bicalutamide

1/I/0S

7 ng/rnL Í7 rricg/mL)

Continued Jeuprolide

1/1/09

67 fig/ml (67 mcg/mL)

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