Cancer Chemotherapy Update Luteinizing-hormone-releasing hormone by tgv36994


									                Hospital Pharmacy
         Volume 37, Number 5, pp 485–487
           2002 Facts and Comparisons

                      Cancer Chemotherapy Update

           Hormone Agonist plus Antiandrogen
              Regimens in the Treatment of
               Advanced Prostate Cancer
                           J. Aubrey Waddell, PharmD, BCOP, Patrick M. Garman, PharmD,* and
                                   Dominic A. Solimando, Jr., MA, FAPhA, FASHP, BCOP

 The increasing complexity of cancer chemotherapy                            Huggins’ determination of the effect of testosterone
 makes it mandatory that pharmacists be familiar with                   deprivation on prostate cancer cells, for which he ultimately
 these highly toxic agents. This column reviews various                 won the Nobel Prize, established the basis for orchiectomy
 issues related to the preparation, dispensing, and admin-              or exogenous estrogens as primary therapy for advanced
 istration of cancer chemotherapy, both commercially                    prostate cancer.3 Diethylstilbestrol, an estrogen analog that
 available and investigational. Questions or suggestions                results in a pharmacological castration, provides a survival
 should be addressed to: Dominic A. Solimando, Jr., Pres-               benefit equivalent to orchiectomy, but fell out of favor due to
 ident, Oncology Pharmacy Services, Inc., 4201 Wilson                   excess cardiovascular mortality.4 Estrogen analogs were
 Boulevard, #110-545, Arlington, VA 22203 or J. Aubrey                  replaced as primary agents for pharmacological castration in
 Waddell, Pharmacy Consultant, HHC, U.S. Army 18th                      prostate cancer therapy by LHRHAs, such as leuprolide and
 MEDCOM (Unit 15281), Box 711, APO AP 96205-0017                        goserelin, which provide similar survival and quality-of-life
 (Seoul, Korea). E-mail:; aubrey.wad-                  outcomes compared with orchiectomy.5,6 mil.                                                   Labrie et al. developed the concept of combining an
 The opinions or assertions contained herein are the private views      LHRHA or orchiectomy with a nonsteroidal antiandrogen,
 of the authors and are not to be construed as official or reflecting   such as flutamide, to block the effects of adrenal androgens
 the views of the U.S. Department of the Army or Department of          on prostate cancer and maximize the effects of pharmaco-
 Defense.                                                               logical castration or orchiectomy.7 This concept has been
     *Patrick M. Garman is Chief, Department of Pharmacy, U.S.
                                                                        variously known as total androgen blockade, combined
 Army 121st General Hospital, Seoul, Korea.
                                                                        androgen blockade, complete androgen blockade, and max-
                                                                        imal androgen blockade. The first large-scale trial to test this
                                                                        concept was the National Cancer Institute (NCI)-sponsored
                                                                        INT-0036, which tested leuprolide plus flutamide against
Regimen: Luteinizing-Hormone-Releasing                                  leuprolide plus placebo for advanced prostate cancer. The
Hormone Agonist (LHRHA) plus Antiandrogen                               leuprolide plus flutamide combination resulted in longer pro-
(see Table 1)                                                           gression-free survival and an increase in median length of
                                                                        survival, though the differences between the treatments were
                                                                        particularly evident for men with minimal disease and good
INDICATIONS                                                             performance status.8 The LHRHA plus antiandrogen regi-
    LHRHA plus antiandrogen regimens are a primary ther-                mens have become widely used over the last decade,
apy for advanced prostate cancer. These regimens are also               though their advantages over an LHRHA or orchiectomy
used, with or without radiotherapy, for patients with recurrent         alone have been recently called into question.2,9,10
prostate cancer or high risk for such recurrence; or as neoad-
juvant therapy prior to surgical resection of prostate cancer.1,2

                                                                                                           Hospital Pharmacy       485
Cancer Chemotherapy Update

                                                          TABLE 1

                                          LHRHA plus Antiandrogen Regimens8,11–16
 Drug                           Dose                   Route of                Administered              Total Dose/
                                                     Administration             on Day(s)                   Cycle

 Leuprolide Acetate for        7.5 mg*                     IM                        1                     7.5 mg
 Depot Suspension
 Goserelin Acetate Implant     3.6 mg                      SQ                        1                     3.6 mg
 Flutamide                   250 mg TID                    PO                       1–28                 21,000 mg
 Bicalutamide                   50 mg                      PO                       1–28                  1400 mg
 Nilutamide                   150 mg**                     PO                       1–28                  4200 mg
 Cycle repeats: Every 28 days until disease progression

 *Crawford et al. administered leuprolide acetate injection 1 mg subcutaneously every day.
 **Nilutamide is administered at a dose of 300 mg per day for the first 28 days of therapy.

DRUG PREPARATION                                                    When given at this dose and schedule, flutamide should
A. Leuprolide Acetate for Depot Suspension                          be taken at the same time each day.
   1. Use a 7.5 mg vial of sterile lyophilized microspheres      D. Bicalutamide
      and reconstitute according to package insert or use a         1. Use 50 mg tablets.
      7.5 mg prefilled dual chamber syringe.                        2. Take one 50 mg tablet each morning or evening, with
   2. Leuprolide acetate for depot suspension is also avail-           or without food.
      able as a 22.5 mg vial and a prefilled dual chamber           3. It is recommended that bicalutamide be taken at the
      syringe for administration every 84 days (3 months)              same time each day.
      and a 30 mg vial and prefilled dual chamber syringe for    E. Nilutamide
      administration every 112 days (4 months).                     1. Use 50 mg tablets.
B. Goserelin Acetate Implant                                        2. Take 3 tablets once daily, with or without food.
   1. Use a 3.6 mg ready-to-use disposable syringe device.          3. It is recommended that nilutamide be taken at the
   2. The goserelin acetate implant is also available as a             same time each day.
      10.8 mg ready-to-use disposable syringe device for
      administration every 84 days (3 months).                   SUPPORTIVE CARE
                                                                 A. Acute Emesis Prophylaxis:8,11,12,16 LHRHA plus antian-
DRUG ADMINISTRATION                                                 drogen regimens cause nausea or vomiting in less than
A. Leuprolide Acetate for Depot Suspension                          15% of patients. Acute emesis prophylaxis is not neces-
   1. Administer by intramuscular injection.                        sary. Patients may require an antiemetic prescription to
B. Goserelin Acetate Implant                                        treat nausea experienced during therapy with LHRHA
   1. Administer by subcutaneous injection into the upper           plus antiandrogen regimens. The following regimens are
      abdominal wall.                                               suggested:
C. Flutamide                                                        1. Prochlorperazine 10 mg PO every 4 to 6 hours as
   1. Use 125 mg capsules.                                             needed, or prochlorperazine 15 mg (extended-release
   2. Take two capsules three times daily at 8-hour intervals,         capsule) every 8 to 12 hours as needed, or prochlor-
      with or without food.                                            perazine 25 mg suppository rectally every 6 hours as
   3. When combined with castration, flutamide 500 mg (4               needed.
   capsules) given once daily appears to be equally effective       2. Thiethylperazine 10 mg PO every 4 to 6 hours as
   in lowering serum prostate specific antigen (PSA) and is            needed.
   not significantly more toxic than conventional dosing.17      B. Hematopoietic Growth Factors: None necessary.

486     Volume 37, May 2002
                                                                                     Cancer Chemotherapy Update

C. Hypersensitivity Precautions: None necessary.                  al ablative therapy before radical prostatectomy: A review. Is
                                                                  it indicated? J Urol. 2000;164:1465–72.

TOXICITIES                                                        3. Lytton B. Prostate cancer: A brief history and the discov-
                                                                  ery of hormonal ablation treatment. J Urol.
A. Cardiovascular: 8,11,12,14,16 Any cardiovascular toxicity,     2001;165:1859–62.
   1.7% to 8%; hot flashes, 13.9% to 70%; peripheral
                                                                  4. Byar DP, Corle DK. Hormone therapy for prostate cancer:
   edema, 11% to 14%.                                             Results of the Veterans Administration Cooperative Urologi-
B. Dermatologic:8,12–16 Breast swelling, 14%; breast tender-      cal Research Group studies. NCI Monogr. 1988;7:165–70.
   ness, 7%; gynecomastia, 1.9% to 24%; pruritus, 0.5% to         5. Seidenfeld J, Samson DJ, Hasselblad V, et al. Single-
   1.8%; rash, 0.9% to 4%.                                        agent androgen suppression in men with advanced prostate
C. Gastrointestinal:8,11,12,14,16 Anorexia, 1.8%; constipation,   cancer: A systematic review and meta-analysis. Ann Intern
                                                                  Med. 2000;132:566–77.
   16% to 22%; diarrhea, 1.8% to 30%; nausea, 5.4% to
   15%; nausea/vomiting, 6.8% to 11.8%.                           6. Potosky AL, Knopf K, Clegg LX, et al. Quality-of-life out-
D. Genitourinary:11,12,14 Decrease in erections, 89%;             comes after primary androgen deprivation therapy: Results
                                                                  from the Prostate Cancer Outcomes Study. J Clin Oncol.
   decreased libido, 2.7% to 91%; hematuria, 6% to 12%;           2001;19:3750–7.
   nocturia, 12% to 14%.
                                                                  7. Labrie F, Dupont A, Belanger A, et al. Combination ther-
E. Hematologic:11 Anemia, 8% to 12%.                              apy with flutamide and castration (LHRH agonist or orchiec-
F. Hepatic:11–16 Abnormal liver function tests, 4.4% to 12%;      tomy) in advanced prostate cancer: A marked improvement
   hepatitis, 0.9% to 1%.                                         in response and survival. J Steroid Biochem.
G. Injection Site Reactions:11 Hypersensitivity, 0.6%; pain,
   0.4% to 1.1%.                                                  8. Crawford ED, Eisenberger MA, McLeod DG, et al. A con-
                                                                  trolled trial of leuprolide with and without flutamide in prosta-
H. Neurologic:11,12,14 Asthenia, 4.5% to 26%; depression,         tic carcinoma. N Engl J Med. 1989;321:419–24.
                                                                  9. Laufer M, Denmeade SR, Sinibaldi VJ, et al. Complete
I. Ocular:14 Poor light/dark adaptation, 10.7% (nilutamide        androgen blockade for prostate cancer: What went wrong? J
only); other visual toxicity, 10.7% (nilutamide only).            Urol. 2000;164:3–9.
J. Other:11,12,14 Dizziness, 4.5% to 14%; dizziness/tiredness,    10.Prostate Cancer Trialists’ Collaborative Group. Maximum
   2.4%; flu syndrome, 6% to 11%; weight loss, 0.9% to            androgen blockade in advanced prostate cancer: An
   1.5%; weight gain, 0.9% to 1.7%.                               overview of the randomised trials. Lancet. 2000;355:1491–8.
K. Pain:11,14 Abdominal pain, 9% to 13%; any pain, 1.8% to        11. Sarosdy MF, Schellhammer PF, Sharifi R, et al. Compar-
   30%; back pain, 23% to 30%; bone pain, 9% to 12%;              ison of goserelin and leuprolide in combined androgen block-
   pelvic pain, 17% to 24%.                                       ade therapy. Urology. 1998;52:82–8.
L. Pulmonary:11,14 dyspnea, 5% to 14%; interstitial pneu-         12.Tyrrell CJ, Altwein JE, Klippel F, et al. A multicenter ran-
   monitis, 4.5% (nilutamide trial only).                         domized trial comparing the luteinizing hormone-releasing
                                                                  hormone analogue goserelin acetate alone and with flu-
                                                                  tamide in the treatment of advanced prostate cancer. J Urol.
PRETREATMENT LABORATORY STUDIES                                   1991;146:1321–6.
NEEDED                                                            13.Boccardo F, Pace M, Rubagotti A, et al. Goserelin acetate
A. Baseline                                                       with or without flutamide in the treatment of patients with
   1. AST/ALT                                                     locally advanced or metastatic prostate cancer. Eur J Can-
                                                                  cer. 1993;29A:1088–93.
   2. Total bilirubin
                                                                  14.Chatelain C, Rousseau V, Cosaert J. French multicentre
DOSAGE MODIFICATIONS                                              trial comparing Casodex (ICI 176,334) monotherapy with
                                                                  castration plus nilutamide in metastatic prostate cancer: A
A. Renal function: None needed.                                   preliminary report. Eur Urol. 1994;26(suppl 1):10–4.
B. Hepatic function: None needed.
                                                                  15.Denis LJ, Keuppens F, Smith PH, et al. Maximal andro-
C. Hematologic: None needed.                                      gen blockade: Final analysis of EORTC phase III trial 30853.
                                                                  Eur Urol. 1998;33:144–51.
REFERENCES                                                        16.Iversen P, Christensen MG, Friis E, et al. A phase III trial
1. National Comprehensive Cancer Network. NCCN prac-              of Zoladex and flutamide versus orchiectomy in the treat-
tice guidelines in oncology: Prostate cancer. [The Complete       ment of patients with advanced carcinoma of the prostate.
Library of Practice Guidelines in Oncology (CD-ROM)]. Ver-        Cancer. 1990;66:1058–66.
sion 2001. Rockledge, PA: National Comprehensive Cancer
Network; 2001.                                                    17.Thrasher JB, Deeths J, Bennett C, et al. Comparative
                                                                  study of the clinical efficacy of two dosing regimens of flu-
2. Scolieri MJ, Altman A, Resnick MI. Neoadjuvant hormon-         tamide. Mol Urol. 2000;4:259–63. n

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