Correspondence

Long-Acting Gonadotropin-Releasing Hormone Implant to Maintain Medical Castration for Two Years in Men with Prostate Cancer

N Engl J Med 1999; 340:1439May 6, 1999

Article

To the Editor:

Medical castration with long-acting gonadotropin-releasing hormone agonists is an effective therapy for men with metastatic prostate cancer.1,2 Initially, these agonists had to be given daily, but depot preparations that can be administered at intervals of one to three months are now available.3,4 We describe here the response to a longer-acting implant releasing the gonadotropin-releasing hormone agonist histrelin (Hydron, Hydro Med Sciences) in men with prostate cancer.

We treated 13 men 65 to 88 years of age who had prostate cancer that extended beyond the prostate capsule with 50 mg of the gonadotropin-releasing hormone agonist histrelin, administered with a cylindrical reservoir drug-release device 30 mm long and 3.5 mm in diameter, inserted subcutaneously in the upper arm with local anesthesia. The in vitro rate of histrelin release from this device is approximately 60 μg daily for at least one year. Five men received one implant, and the remaining eight received two implants.

To prevent the transient increase in the secretion of luteinizing hormone and testosterone when gonadotropin-releasing hormone agonist therapy is begun1,2 — a response known as the flare phenomenon — the men received an antiandrogen starting two weeks before insertion of the implant and continuing for three months thereafter. Nine men received flutamide, and four cyproterone acetate. During therapy, blood samples were collected for measurements of serum luteinizing hormone, testosterone, and prostate-specific antigen and radionuclide bone scanning was repeated every six months. The study was approved by the Human Investigation Committee of Shaare Zedek Medical Center, and all the men gave written informed consent.

Serum luteinizing hormone was measured by enzyme immunoassay (Abbott Laboratories), testosterone was measured by radioimmunoassay (Diagnostic Products), and prostate-specific antigen was measured by an immunoradiometric assay (BYK, Sangtec Diagnostica). The lower limits of sensitivity for the luteinizing hormone and testosterone assays were 0.1 IU per liter and 10 ng per deciliter (0.35 nmol per liter), respectively.

Serum prostate-specific antigen concentrations in these men before treatment ranged from 29 to 931 ng per milliliter (normal value, ≤4). The values began to decrease during antiandrogen therapy and continued to fall thereafter, reaching values of <4 ng per milliliter in all the men after three months. In all the men, serum luteinizing hormone and testosterone concentrations were undetectable after 1 month of treatment and remained so after 17 to 24 months.

Three men had hot flashes, but there were no other adverse effects. Eleven of the 13 men remain in remission, with serum prostate-specific antigen concentrations in the normal range, but the concentrations of serum prostate-specific antigen began to rise after 11 months of treatment in 2 men. This histrelin implant is effective in maintaining the suppression of luteinizing hormone and testosterone secretion for at least two years in men with prostate cancer.

Irving M. Spitz, M.D.
Boris Chertin, M.D.
Tzina Lindenberg, M.A.
Amicur Farkas, M.D.
Shaare Zedek Medical Center, Jerusalem 91031, Israel

4 References

1. 1

   Walsh PC. Physiologic basis for hormonal therapy in carcinoma of the prostate. Urol Clin North Am 1975;2:125-140
   Medline

2. 2

   Labrie F. Endocrine therapy of prostate cancer: optimal form and timing. J Clin Endocrinol Metab 1995;80:1066-1071
   CrossRef | Web of Science | Medline

3. 3

   Crawford ED, Eisenberger MA, McLeod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989;321:419-424[Erratum, N Engl J Med 1989;321:1420.]
   Full Text | Web of Science | Medline

4. 4

   Dijkman GA, del-Moral PF, Plasman JW, et al. A new extra long acting depot preparation of the LHRH analogue Zoladex: first endocrinological and pharmacokinetic data in patients with advanced prostate cancer. J Steroid Biochem Mol Biol 1990;37:933-936
   CrossRef | Web of Science | Medline

Citing Articles (13)

Citing Articles

1. 1

   Jonathan M. Ricker, William F. Foody, Nathan M. Shumway, Janet C. Shaw. (2010) Drug-Induced Liver Injury Caused by the Histrelin (Vantus®) Subcutaneous Implant. Southern Medical Journal 103:1, 84-86
   CrossRef

2. 2

   Peter Schlegel. (2009) A review of the pharmacokinetic and pharmacological properties of a once-yearly administered histrelin acetate implant in the treatment of prostate cancer. BJU International 103, 7-13
   CrossRef

3. 3

   Samar Rahhal, Erica Eugster. (2008) Histrelin implant for the treatment of central precocious puberty. Pediatric Health 2:2, 141-145
   CrossRef

4. 4

   Kiyohiro HOUKIN, Tadashi NONAKA, Shinnichi OKA, Izumi KOYANAGI. (2005) Inadequate Website Disclosure of Surgical Outcome of Intracranial Aneurysms. Neurologia medico-chirurgica 45:9, 448-453
   CrossRef

5. 5

   Yoichi AKIBA, Toshiaki TAZAWA, Yaichi AKIBA, Toshiaki ABE. (2003) A Review of 65 Cases of Unruptured Aneurysms under Observation: The Risks of Untreated Aneurysm under 5 mm in Size.. Surgery for Cerebral Stroke 31:1, 18-23
   CrossRef

6. 6

   Shigeaki Kobayashi, Akira Teramoto. (2002) The Current State of Neurosurgery in Japan. Neurosurgery 51:4, 864-870
   CrossRef

7. 7

   Katsumi MATSUMOTO, Katsuhito AKAGI, Makoto ABEKURA, Tateo SAKAGUCHI, Takahiro TOMISHIMA, Masayuki AOKI, Kazumi YAMAMOTO, Eiji KOHMURA, Amami KATO, Toshiki YOSHIMINE. (2002) Long-term Follow-up after Treatment for Cerebrovascular Disease. Semi-long-term Follow-up Results for the Treatment of the Unruptured Cerebral Aneurysms.. Surgery for Cerebral Stroke 30:2, 83-87
   CrossRef

8. 8

   Yoshihide NAGAMINE, Hiroaki SHIMIZU, Teiji TOMINAGA, Masayuki EZURA, Akira TAKAHASHI, Takashi YOSHIMOTO. (2001) Therapeutic Strategy for Unruptured Cerebral Aneurysms. Clinical Management of Asymptomatic Unruptured Cerebral Aneurysms.. Surgery for Cerebral Stroke 29:3, 166-171
   CrossRef

9. 9

   Katsumi MATSUMOTO, Katsuhito AKAGI, Makoto ABEKURA, Kazumi YAMAMOTO, Yoshikazu NAKAJIMA, Amami KATO, Eiji KOHMURA, Toshiki YOSHIMINE. (2001) Therapeutic Strategy for Unruptured Cerebral Aneurysms. Problems Underlying the Treatment of Unruptured Cerebral Aneurysms Investigated by Comparing the Prognosis of Observed Patients and Surgically Treated Patients.. Surgery for Cerebral Stroke 29:3, 155-159
   CrossRef

10. 10

    JACKSON E. FOWLER, JAMES E. GOTTESMAN, C. FREDRIC REID, GERALD L. ANDRIOLE, MARK S. SOLOWAY. (2000) SAFETY AND EFFICACY OF AN IMPLANTABLE LEUPROLIDE DELIVERY SYSTEM IN PATIENTS WITH ADVANCED PROSTATE CANCER. The Journal of Urology 164:3, 730-734
    CrossRef

11. 11

    JACKSON E. FOWLER, JAMES E. GOTTESMAN, C. FREDRIC REID, GERALD L. ANDRIOLE, MARK S. SOLOWAY. (2000) SAFETY AND EFFICACY OF AN IMPLANTABLE LEUPROLIDE DELIVERY SYSTEM IN PATIENTS WITH ADVANCED PROSTATE CANCER. The Journal of Urology730-734
    CrossRef

12. 12

    BORIS CHERTIN, IRVING M. SPITZ, TZINA LINDENBERG, NURIT ALGUR, TAMI ZER, PETR KUZMA, ALFRED J. MOO YOUNG, RAPHAEL CATANE, AMICUR FARKAS. (2000) AN IMPLANT RELEASING THE GONADOTROPIN HORMONE-RELEASING HORMONE AGONIST HISTRELIN MAINTAINS MEDICAL CASTRATION FOR UP TO 30 MONTHS IN METASTATIC PROSTATE CANCER. The Journal of Urology 163:3, 838-844
    CrossRef

13. 13

    BORIS CHERTIN, IRVING M. SPITZ, TZINA LINDENBERG, NURIT ALGUR, TAMI ZER, PETR KUZMA, ALFRED J. MOO YOUNG, RAPHAEL CATANE, AMICUR FARKAS &NA;. (2000) AN IMPLANT RELEASING THE GONADOTROPIN HORMONE-RELEASING HORMONE AGONIST HISTRELIN MAINTAINS MEDICAL CASTRATION FOR UP TO 30 MONTHS IN METASTATIC PROSTATE CANCER. The Journal of Urology838
    CrossRef