Challenges with Luteinizing Hormone-Releasing Hormone Agonists: Flare and Surge

TREATMENT OF SYMPTOMATIC PROSTATE CANCER PATIENTS Challenges with Luteinizing Hormone-Releasing Hormone Agonists: Flare and Surge Michael K. Brawer, MD Northwest Prostate Institute, Northwest Hospital, Seattle, WA Although the mechanism behind the role of circulating androgens in the development and progression of prostatic carcinoma is not totally clear, androgen deprivation therapy remains a mainstay of treatment for this cancer. As surgical orchiectomy has fallen out of favor and the use of estrogens has been associated with cardiac toxicity, pharmacologic approaches have become even more common, namely, the use of luteinizing hormone-releasing hormone (LHRH) agonists. These agents, however, are not without side effects; the primary ones are the “flare” phenomenon, which stems from an initial surge in testosterone level and can include increased pain at metastatic sites, spinal cord compression, and even sudden death. Some studies have reported increased morbidity with the use of LHRH agonists, and while the significance of flare is not entirely known at this point, data seem to indicate that, at least in men with advanced disease, avoiding flare may be prudent. [Rev Urol. 2004;6(suppl 7):S12-S18] © 2004 MedReviews, LLC Key words: Dihydrotestosterone • Luteinizing hormone-releasing hormone • Flare • Prostatic carcinoma ndrogen deprivation therapy remains a mainstay in the treatment of men with various stages of prostatic carcinoma. In the treatment of advanced disease this remains the main therapeutic approach. Moreover, changes in the presentation of prostate cancer and increased recognition of failure of primary therapy have resulted in greater utilization of androgen deprivation therapy in a variety of clinical settings. A S12 VOL. 6 SUPPL. 7 2004 REVIEWS IN UROLOGY Challenges with LHRH Agonists It is well established that circulating androgens are a central prerequisite for the growth of the normal prostate and by extension allow development of clones of epithelial cells that can undergo malignant transformation; however, the action of androgens on the process of carcinogenesis is not clear. Most authorities believe that androgen allows cellular growth and division and promotes carcinogenesis. Although we generally relate the male hormone testosterone to stimulation of the prostate, it is well recognized that it is more precisely the more active metabolite dihydrotestosterone (DHT) that actually is a much greater stimulus of prostatic tissue. DHT forms by the reduction of testos- these incidental small carcinomas to larger cancers; this may allow for the establishment of clones inheriting the genetic changes that are prerequisite for development of the aggressive phenotype. That greater cell proliferation may allow for increases in genetic instability has been established.6 This represents the basis of concern about the use of androgen supplementation in the hypogonadal man. Although a number of studies have looked at serum hormone levels in prostatic carcinoma, no pattern has been identified. Indeed, there are as many studies demonstrating decreased levels in men with cancer as there are those showing increased levels.7-16 Three studies looked at DHT but failed Although a number of studies have looked at serum hormone levels in prostatic carcinoma, no pattern has been identified. terone by the enzyme 5
-reductase.1 As with testosterone, the role of DHT in the promotion of prostate cancer is not known. However, one natural phenomenon is of great interest. Prostatic carcinoma has never been shown to develop in pseudohermaphrodite men who have an intrinsic deficiency of 5
-reductase. Both testosterone and DHT bind to the same androgen receptor protein, although DHT has a much higher binding affinity.2 The DHT receptor complex within the prostate cell migrates to the nucleus, where it binds to specific sites on the DNA, resulting in increased transcription.3,4 While the factors associated with the development of this clinically latent carcinoma and its progression to the clinically recognized aggressive phenotype is unknown, it has been postulated that it follows a multistep process of carcinogenesis.5 Androgenic stimulation may be an important factor in the progression of to demonstrate a correlation between DHT level and prostate cancer.13,14,16 Nomura and associates17 demonstrated elevated testosterone-to-DHT ratio in men with prostate cancer. BarrettConnor and coworkers7 found a correlation between prostate cancer and serum androstenedione levels. Hsing and Comstock18 demonstrated elevated luteinizing hormone (LH) levels and also reinforced Nomura’s findings. A meta-analysis has been conducted on prostate cancer incidence and serum levels of androgens.19 There was a 2.34-fold increased risk of prostate cancer in men with upper-quartile testosterone levels relative to those with levels in the lower quartile. In a population-based study, levels of testosterone, DHT, estrone, estradiol, prolactin, follicle-stimulating hormone (FSH), and LH were compared in 103 men with prostate cancer and age- and race-matched controls.19 In another study, Hill and associates20 compared hormone levels in South African and North American blacks. Estradiol and estrone levels were higher in the South African men, and testosterone levels were higher in the American men. These authors also studied the effect of diet on the hormone levels.21 When North American men switched to a vegetarian diet, there was decreased excretion of androgens and estrogens. The opposite effect occurred when a Western diet was adopted by the South African participants. Additional efforts to explain the racial difference in prostatic carcinoma have involved measurement of various hormones. In general, these studies have shown increased levels of androgens in higher-risk populations such as African Americans.9,11,15,22,23 Lookingbill and associates23 studied DHT metabolites as a marker of 5
-reductase activity. They demonstrated a 2-fold increase in DHT level in Caucasians compared with Chinese men. Similarly, deJong and associates9 demonstrated increased testosterone and estradiol levels in Dutch men compared with Japanese men. In an important study, Ross and associates22 demonstrated higher testosterone levels in young African Americans compared with Caucasians as well as lower 5
-reductase activity in Japanese men compared with blacks and whites. It would seem obvious to study hormone levels in the tissue of men with both benign prostatic hyperplasia (BPH) and prostatic carcinoma. However, numerous methodologic problems, including delineation of actual histology of the tissue in question, variance in methods used to determine hormone levels, and artifacts of tissue acquisitions (such as heat related to transurethral resection) have resulted in tremendous confusion in the reported studies.24-27 The best study to date, reported by Walsh and coworkers24 demonstrated there was no difference in tissue DHT levels VOL. 6 SUPPL. 7 2004 REVIEWS IN UROLOGY S13 Challenges with LHRH Agonists continued between BPH and normal peripheral prostatic tissue. There exists a paucity of data with respect to androgen levels in prostatic carcinoma. Geller and associates28 reported lower DHT values in men with untreated prostate cancer than in men with BPH. Geller and colleagues29,30 demonstrated significant reduction in DHT levels after hormonal ablation in prostate cancer tissue. Utilizing immunohistochemical methodology, Saudi and Barrack31 demonstrated extensive heterogeneity in quantitation of the androgen receptor following androgen deprivation therapy. In a number of animal models, it has been demonstrated that exogenous androgens stimulate established prostate cancer in a dose-dependent fashion.32,33 Testosterone given to patients with advanced metastatic prostate cancer results in severe pain at sites of bone metastases.34 This phenomenon has been widely recognized during the testosterone surge and resulting flare associated with LHreleasing hormone (LHRH) agonists.35-46 Historically, surgical orchiectomy was the initial therapeutic approach. This resulted in immediate castrate levels of testosterone and must be considered, in many respects, the gold standard. Unfortunately, because of the invasiveness of the procedure and its psychologic effects, this approach has fallen into disfavor as pharmacologic approaches have evolved. The use of estrogens has provided results similar to those seen with orchiectomy; however, cardiac toxicity resulted in their being considered unacceptable in most situations. The major advance in the pharmacologic approach to hormonal therapy in men with prostatic carcinoma was the development of the LHRH agonist. Ultimately, castrate levels of testosterone are achieved with the LHRH agonist; however, this occurs follow- S14 VOL. 6 SUPPL. 7 2004 ing an initial surge in testosterone resulting from increased secretion of LH. In addition to the biochemical surge in the testosterone level, the concept of associated clinical sequelae became known as “flare.” The terms “flare” and “surge” have been confusingly interchanged in the literature. Flare should be limited to mean the clinical manifestations resulting from increased testosterone level. These can include exacerbation or development of symptoms such as bone pain, urinary blockage, and spinal cord compression. These occur within the first few weeks after institution of LHRH agonist therapy.35,36,39 Surge, on the other hand, represents the transient increase in LH level and resulting stimulation of FSH, DHT, stimulation, caused by competitive binding to LHRH receptors in the pituitary. This binding occurs with a higher affinity than intrinsic LHRH. The use of an LHRH agonist results in increase in LH and FSH release initially.49 Within a few days, the LHRH receptor in the anterior pituitary becomes desensitized and subsequently down-regulated, resulting in suppression of LH and FSH and thus achievement of castrate levels of testosterone. The Flare Phenomenon The clinical flare phenomenon results from the initial increase in LH and, potentially, FSH levels. This increased testosterone production not only results in stimulation of androgen- The use of estrogens has provided results similar to those seen with orchiectomy; however, cardiac toxicity resulted in their being considered unacceptable in most situations. and testosterone. The resulting rise in serum prostate-specific antigen (PSA) level as well as prostatic acid phosphates (PAP) may also be considered part of the surge phenomenon. Luteinizing hormone-releasing hormone (LHRH) agonists generated in the hypothalamus bind to receptors on the anterior pituitary and stimulate the release of both luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH circulates to the testes and in the Leydig cell stimulates testosterone production.47 FSH, which has been reported to be a potential stimulus of prostate cancer, binds to receptors on cells in the testes and, more important, in the prostate. It is suggested to cause stimulation via an autocrine/paracrine mechanism.48 While the mechanism of action of LHRH agonists is not definitively established, they do result in paradoxical suppression of testosterone REVIEWS IN UROLOGY dependent cells but also may be sufficient to result in proliferation of androgen-sensitive clones. The surge in androgens has also been suggested to result in increased prostate cellular proliferation and angiogenesis.50 Quayum and coworkers51 have suggested that in addition, there may be a direct LHRH stimulation owing to LHRH receptors on prostate cancer cells. Flare was first reported by Faure and colleagues in 1983.52 They reported that almost 10% of patients receiving an early LHRH agonist had increasing bone pain during the first week of treatment. Of greater concern, Kahan and coworkers46 a year later reported 2 cases of sudden death following dramatic disease flare and spinal cord compression. Symptoms developed within the first couple of days following injection. In the initial trial resulting in the eventual approval of leuprolide Challenges with LHRH Agonists Peak at 300% at 24 hrs Peak day 3 LH back to baseline by day 29 Baseline day 7 Testosterone Pain LH LHRH-agonist administered Castrate at 3 weeks Pain flare generally resolved at 1 week Pain begins Pain peaks at 12 hours at 36 hours Figure 1. Bone pain and other symptoms associated with flare occurred within 12 hours of treatment with a luteinizing hormone-releasing hormone (LHRH) agonist but generally resolved by 1 week. Data from Kreis W et al.38 and Waxman J et al.39 LH, luteinizing hormone. Mahler54 also provided a compilation of the literature showing that flare occurred in 4.2% to 33% of men treated with LHRH agonists. Clinical Implications of Flare and Surge The manifestation of flare depends on the extent and distribution of cancer. Obviously, cancer confined to the prostate would manifest itself with increasing urinary obstructive Figure 2. Use of antiandrogens in addition to luteinizing hormone-releasing hormone (LHRH) agonists does not decrease the surge associated with increase in testosterone and luteinizing hormone (LH) levels. Adapted with permission from Kuhn JM, Billebaud T, Navratil H, et al. Prevention of the transient adverse effects of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen [nilutamide]. N Engl J Med. 1989;321:413-418. Copyright © 2004 Massachusetts Medical Society. All rights reserved. LHRH + antiandrogen LHRH alone 40 20 16 Plasma LH Levels (IU/L) Plasma Testosterone (nmol/L) acetate, 7% of patients experienced increased bone pain during the initial weeks of treatment; in contrast, this was seen in only 1% of a controlled population treated with diethylstilbestrol (DES).53 Chemical evidence of this was confirmed with the realization that a significant number of men had increased levels of PAP initially (PSA measurement was not utilized in this study). Waxman and associates39 also described exacerbation or onset of bone pain and other symptoms within 12 hours of treatment in 37% of men who received another LHRH agonist (Figure 1). Thompson and coworkers36 reported on an additional 2 patients with sudden death following institution of LHRH agonist therapy. In their report, they noted 6 other studies in which 15 deaths occurred within the first few weeks of institution of LHRH agonist therapy.38,40,44-46,53 Additionally, these authors cited 9 studies demonstrating symptomatic flare during LHRH therapy.35-38,40-42,45,53 Disease flare, including symptoms such as worsening skeletal pain, flank pain, urinary tract obstruction, lymphedema, and neurologic symptoms, was experienced by 10.9% of the patients. symptoms. With more cephalad extension, ureteral obstruction and hydronephrosis may ensue. This can result in renal failure. Dramatic and significant manifestation of flare may occur in metastatic bone sites, where severe pain may occur. The most serious consequence, of course, is spinal cord compression resulting from expansion of spinal metastasis. Paraplegia or quadriplegia and death have been reported with this phenomenon.36,46 Surge manifestation includes, obviously, the increase in testosterone level, but more readily measured is increase in PSA and PAP levels. These levels generally begin to increase a week following institution of the LHRH agonist. The long-term consequence of flare remains debated. Given the heterogeneity of prostate cancer, definitive conclusions are lacking; there exists, however, some evidence that disease flare may result in earlier progression, and the decreased survival that occurs in long-term studies of LHRH agonists provides the most compelling evidence. In the initial 12 8 4 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 18 22 29 1 2 3 4 5 6 7 Day of Treatment 8 9 10 11 12 13 14 18 22 29 Day of Treatment VOL. 6 SUPPL. 7 2004 REVIEWS IN UROLOGY S15 Challenges with LHRH Agonists continued 100 80 Percent 60 40 20 0 0 6 12 18 24 30 42 36 Months after Registration Treatment Leuprolide + placebo Leuprolide + flutamide At Risk Treatment Failure Median Progression-Free Survival 300 303 209 189 13.9 16.5 Figure 3. Data from the Southwest Oncology Group study 0036, which compared leuprolide alone with leuprolide plus flutamide. Progression-free survival rate and median length of survival were greater in patients who received both agents. Adapted with permission from 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. Copyright © 2004 Massachusetts Medical Society. All rights reserved. Leuprolide Study Group, there was a higher incidence of early disease progression in men treated with leuprolide acetate than in those treated with DES.43 Bruchovsky and associates55 suggested that this difference may reflect disease flare, which is not seen in men treated with estrogens. Other studies, in which total androgen blockade was compared with LHRH agonist treatment alone, did show greater overall improvement in the former group, and again the theory was that prevention of flare was the explanation.35,56 It should be emphasized that use of antiandrogens does not decrease the surge associated with increase in testosterone and LH levels (Figure 2). Perhaps the most significant trial to suggest that the flare phenomenon S16 VOL. 6 SUPPL. 7 2004 is real was the Southwest Oncology Group study 0036, in which men with stage D2 prostate cancer received either leuprolide alone or leuprolide plus flutamide (Figure 3).35 The trial demonstrated that the progression-free survival rate and the median length of survival were greater in the combination-treatment arm. Moreover, the odds of improvement in symptoms were significantly greater in the combination group at 4 weeks suggesting again that flare was significant. PAP levels were significantly lower as soon as 4 weeks after initiation of therapy in the combination arm. The progression-free survival differential was apparent within 3 months of initiating therapy. A meta-analysis of studies of total androgen blockade57 suggests that, REVIEWS IN UROLOGY again, some survival benefit occurs in men treated with an LHRH agonist and an anti-androgen compared with an LHRH agonist alone. Several longterm follow-up studies, however, such as that reported by the Agency for Health Care Policy and Research, demonstrated no long-term survival benefit with total androgen blockade.58 Given these results, we can provide no definitive answer to the clinician as to the significance of flare. It does seem intuitive, however, that at least in men with advanced prostate cancer there exists the chance for significant morbidity associated with flare. Thus in less clinically apparent advanced disease (men who may harbor occult metastatic deposits), avoiding flare may be advantageous. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Bruchovsky N, Wilson JD. The conversion of testosterone to 5-alpha-androstan-17-beta-ol3-one by rat prostate in vivo and in vitro. J Biol Chem. 1968;243:2012-2021. Grino PB, Griffin JE, Wilson JD. Testosterone at high concentrations interacts with the human androgen receptor similarly to dihydrotestosterone. Endocrinology. 1990;126:1165-1172. Canovatchel WJ, Imperato-McGinley J. Benign prostatic hyperplasia: pathogenesis and the role of medical management. Geriatr Nephrol Urol. 1992;2:1-23. Wilson JD. Syndromes of androgen resistance. Biol Reprod. 1992;46:168-173. Carter HB, Piantadosi S, Isaacs JT. Clinical evidence for the implications of the multistep development of prostate cancer. J Urol. 1990; 143:742-746. Whittemore AS, Keller JB, Betensky R. Lowgrade, latent prostate cancer volume: predictor of clinical cancer incidence? J Natl Cancer Inst. 1991;83:1231. Barrett-Connor E, Garland C, McPhillips JB, et al. A prospective, population-based study of androstenedione, estrogens, and prostatic cancer. Cancer Res. 1990;50:169-173. Severson RK, Grove JS, Nomura AM, Stemmermann GN. Body mass and prostatic cancer: a prospective study. BMJ. 1988; 297:713-715. de Jong FH, Oishi K, Hayes RB, et al. Peripheral hormone levels in controls and patients with prostatic cancer or benign prostatic hyperplasia: results from the Dutch-Japanese case-control study. Cancer Res. 1991;51:3445-3450. Henderson BE. Summary report of the sixth symposium on cancer registries and epidemiology in the Pacific Basin. J Natl Cancer Inst. 1990;82:1186-1190. Hammond GL, Kontturi M, Vihko P, Vihko R. Serum steroids in normal males and patients with prostatic disease. Clin Endocrinol (Oxf). Challenges with LHRH Agonists 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 1978;9:113-121. Ghanadian R, Rugh CM, O’Donoghue EPN. Serum testosterone and dihydrotestosterone in carcinoma of the prostate. Br J Cancer. 1979;39:696-699. Ahluwalia B, Jackson MA, Jones GW, et al. Blood hormone profiles in prostate cancer patients in high-risk and low-risk populations. Cancer. 1981;48:2267-2273. Zumoff B, Levin J, Strain GW, et al. Abnormal levels of plasma hormones in men with prostate cancer: evidence toward a “two-disease” theory. Prostate. 1982;3:579-588. Hill P, Wynder EL, Garbaczewski L, Walker AR. Effect of diet on plasma and urinary hormones in South African black men with prostatic cancer. Cancer Res. 1982;42:3864-3869. Meikle AW, Smith JA, and West DW. Familial factors affecting prostate cancer risks and plasma sex-steroid levels. Prostate. 1985;6:121-128. Nomura A, Heilbrun LK, Stemmermann GN, Judd HL. Prediagnostic serum hormones and the risk of prostate cancer. Cancer Res. 1988; 48:3515-3517. Hsing A, Comstock G. Serum hormone and risk of subsequent prostate cancer. Am J Epidemiol. 1989;130:829. Slater S, Oliver RTD. Testosterone: its role in the development of prostate cancer and potential risks from use as hormone replacement therapy. Drugs Aging. 2000;17:431-439. Hill P, Wynder EL, Garnes H, Walker AR. Environmental factors, hormone status, and prostatic cancer. Prev Med. 1980;9:657-666. Hill P, Wynder EL, Garbaczewski L, et al. Diet and urinary steroids in black and white North American men and black South African men. Cancer Res. 1979;39:5101-5105. Ross RK, Bernstein L, Lobo RA, et al. 5-alphareductase activity and risk of prostate cancer among Japanese and US white and black males. Lancet. 1992;339:887-889. Lookingbill DP, Demers LM, Wang C, et al. Clinical and biochemical parameters of andro- 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. gen action in normal healthy Caucasian versus Chinese subjects. J Clin Endocrinolm Metab. 1991;72:1242-1248. Walsh PC, Hutchins GM, Ewing LL. Tissue content of dihydrotestosterone in human prostatic hyperplasia is not supranormal. J Clin Invest. 1983;72:1772-1777. Bruchovsky N, Lieskovsky G. Increased ratio of 5-alpha-reductase: 3-alpha-(beta)-hydroxysteroid dehydrogenase activities in the hyperplastic human prostate. J Endocrinol. 1979; 80:289-301. Belis JA. Methodologic basis for the radioimmunoassay of endogenous steroids in human prostatic tissue. Invest Urol. 1980;17:332-336. Wilkin RP, Bruchovsky N, Shnitka TK, et al. Stromal 5-alpha-reductase activity is elevated in benign prostatic hyperplasia. Acta Endocrinol. 1980;94:284-288. Geller J, Albert J, Loza D, et al. DHT concentrations in human prostate cancer tissue. J Clin Endocrinol. 1978;46:440-444. Geller J, Albert JD, Nachtsheim DA, Loza D. Comparison of prostatic cancer tissue dihydrotestosterone levels at the time of relapse following orchiectomy or estrogen therapy. J Urol. 1984;132:693-696. Geller J, Albert JD. DHT in prostate cancer tissue— a guide to management and therapy. Prostate. 1985;6:19-25. Saudi MV, Barrack ER. Image analysis of androgen receptor immunostating in metastatic prostate cancer. Heterogeneity as a predictor of response to hormonal therapy. Cancer. 1993; 71:2574-2580. van Weerden WM, van Steenbrugge GJ, van Kreuningen A, et al. Assessment of the critical level of androgen for growth response of transplantable human prostatic carcinoma (PC-82) in nude mice. J Urol. 1991;145:631-634. Manni A, Santen RJ, Boucher AE, et al. Androgen depletion and repletion as a means of potentiating the effect of cytotoxic chemotherapy in advanced prostate cancer. J Steroid Biochem. 1987;27:551-556. Fowler JE Jr, Whitmore EF Jr. The response of metastatic adenocarcinoma of the prostate to exogenous testosterone. J Urol. 1981;126:372375. 35. 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. 36. Thompson IM, Zeidman EJ, Rodriguez FR. Sudden death due to disease flare with luteinizing hormone-releasing hormone agonist therapy for carcinoma of the prostate. J Urol. 1990;144:1479-1480. 37. Smith JA, Glode LM, Wettlauger JN. Clinical effects of gonadotropin-releasing hormone analogue in metastatic carcinoma of prostate. Urology. 1985;25:106. 38. Kreis W, Ahmann FR, Jordan VC, et al. Oestrogen pre-treatment abolishes luteinising hormone-releasing hormone testosterone stimulation. Br J Urol. 1988;62:352-354. 39. Waxman J, Man A, Hendry WF, et al. Importance of early tumour exacerbation in patients treated with long acting analogues of gonadotropin releasing hormone for advanced prostatic cancer. Br Med J. 1985;291:1387-1388. 40. Kuhn JM, Billebaud T, Navratil H, et al. Prevention of the transient adverse effects of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide). N Engl J Med. 1989;321:413-418. 41. Waxman J. A review of the Hammersmith Hospital, St. Bartholomew's Hospital and Institute of Urology studies of buserlin in advanced prostatic cancer. Am J Clin Oncol. 1988;11(suppl):S16-S18. 42. Trachtenberg J. The treatment of metastatic prostatic cancer with a potent luteinizing hormone releasing hormone analogue. J Urol. 1983; 129:1149-1152. 43. The Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. 34. Main Points • While the factors associated with the development of clinically latent prostatic carcinoma and its progression to the aggressive phenotype is unknown, androgenic stimulation may be an important factor; this has led to the development of hormonal therapy as a mainstay of treatment for prostate cancer. • The major advance in the pharmacologic approach to hormonal therapy in men with prostatic carcinoma was the development of the luteinizing hormone-releasing hormone (LHRH) agonist, which is able to achieve levels of testosterone similar to those achieved with orchiectomy. • On initiation of LHRH agonist treatment, there is an initial surge in testosterone resulting from increased secretion of luteinizing hormone. The associated clinical sequelae, which include symptoms such as worsening skeletal pain, urinary tract obstruction, lymphedema, and neurologic symptoms, are known as “flare” and have been noted in up to 33% of patients. • The most serious consequence of flare is spinal cord compression resulting from expansion of spinal metastases; paraplegia or quadriplegia and even death have been reported with this phenomenon. • Some data indicate that flare may result in earlier cancer progression; the decreased survival that occurs in long-term studies of LHRH agonists provides the most compelling evidence. • While some studies have shown that combining anti-androgen therapy with LHRH agonist treatment can confer a survival benefit, others have shown no such advantage. Presently, it appears that flare is best avoided in those with advanced metastatic disease. VOL. 6 SUPPL. 7 2004 REVIEWS IN UROLOGY S17 Challenges with LHRH Agonists continued 44. 45. 46. 47. 48. S18 N Engl J Med. 1984;311:1281-1286. Klign JG, de Voogt HJ, Schroder FH, de Jong FH. Combined treatment with buserelin and cyproterone acetate in metastatic prostatic carcinoma. Lancet. 1985;2:493. Peeling WB. Phase III studies to compare goserelin (Zoladex) with orchiectomy and with diethylstilbestrol in treatment of prostatic carcinoma. Urology. 1989;33(suppl 5):45-52. Kahan A, Delrieu F, Amor B, et al. Disease flare induced by D-Trp6-LHRH analogue in patients with metastatic prostatic cancer. Lancet. 1984; 1:971-972. Swerdloff RS, Wang C. Physiology of hypothalamic pituitary function. In: Walsh PC, Vaughan ED, Retik AB, et al, eds. Campbell’s Urology. 7th ed. Philadelphia, PA: WB Saunders Company; 1998:1239-1253. Ben-Josef E, Yang SY, Ji TH, et al. Hormonerefractory prostate cancer cells express func- VOL. 6 SUPPL. 7 2004 49. 50. 51. 52. 53. REVIEWS IN UROLOGY tional follicle-stimulating hormone receptor (FSHR). J Urol. 1999;161:970-976. Amgen and Praecis. Data on file. Zagars GK, Pollack A, von Eschenback AC. Serum tesosterone—a siginificant determinant of metastatic relapse for irradiated localized prostate cancer. Urology. 1997;49:327-334. Quayum A, Gullick W, Clayton RC, et al. The effects of gonadotropin releasing hormone analogues in prostate cancer are mediated through specific tumour receptors. Br J Cancer. 1990; 62:96-99. Faure N, Lemay A, Laroche B, et al. Preliminary results on the clinical efficacy and safety of androgen inhibition by an LHRH agonist alone or combined with an antiandrogen in the treatment of prostatic carcinoma. Prostate. 1983 4:601-624. The Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. 54. 55. 56. 57. 58. N Engl J Med. 1984;311:1281-1286. Mahler, C. Is disease flare a problem? Cancer. 1993;72:3799-3802. Bruchovsky N, Goldenberg SL, Akakura K, Rennie PS. Luteinizing hormone-releasing hormone agonists in prostate cancer. Cancer. 1993; 72:1685-1691. Labrie F, et al. Rationale for maximal androgen withdrawal in the therapy of prostate cancer. Baillieres Clin Obstet Gynaecol. 1988;3:597-619. Prostate Cancer Trialists Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomized trials. Lancet. 2000;355:1491-1498. Agency for Health Care Policy and Research. Results and conclusions II: combined androgen blockade. In: Relative Effectiveness and Cost Effectiveness of Methods of Androgen Suppression in the Treatment of Advanced Prostate Cancer. US Dept of Health and Human Services; 1999:73-96.