Comparative Analysis of Luteinizing Hormonereleasing Hormone

ICINE IN THE USE OF LHRH MALDONADO PIJUAN

Evidence-based medicine: comparative analysis of luteinizing hormone-releasing hormone analogues in combination with external beam radiation and surgery in the treatment of carcinoma of the prostate BJUIBJU INTERNATIONAL Santiago Vilar González* and Xavier Maldonado Pijuan† *Radiation Oncology Department, Instituto Medicina Oncológica y Molecular de Asturias, Oviedo, †Radiation Oncology Department, Hospital General Vall d’Hebrón, Barcelona, Spain Accepted for publication 21 July 2010

OBJECTIVE What’s known on the subject? and What does the study add? Luteinizing hormone-releasing hormone analogues are a cornerstone in the management • To study whether luteinizing hormone- of many clinical situations in prostate cancer patients. The multiplicity of drugs make it releasing hormone (LHRH) analogues are difficult to decide which is the best drug to prescribe to each patient. Whether or not the agents of the same pharmacological class, different luteinizing hormone-releasing hormone analogues belong to the same drug i.e. whether they have the same clinical class is only merely supposed. effect, using an evidence-based medicine approach. This study adds a systematic review of the literature in order to determine whether or not the luteinizing hormone-releasing hormone analogues available for prescription belong to the same drug class (same family, similar chemical structure, mechanism of action, and efficacy). The current evidence available is not enough to support a presumed drug class MATERIAL AND METHODS effect of the various analogues in the treatment of prostate carcinoma. • We reviewed the evidence on the alleged ‘drug class effect’ among analogues and the existing bibliographic support for their use in many other issues related to therapeutic CONCLUSION various medical indications. We used management either with analogues alone, or PubMed as the main search source. Evidence in combination with radiation therapy and • The current available evidence is not level and degree of recommendation were surgery. enough to support a presumed class effect assigned to each conclusion based on the • Direct comparisons do not allow definitive of the drug among the different analogues ‘Scottish Intercollegiate Guidelines Network’. conclusions to be reached. Indirect evidence in the treatment of prostate carcinoma in its is obtained from randomized studies various clinical situations. comparing the different LHRH analogues RESULTS with other treatments used to obtain androgen deprivation. Other issues related KEYWORDS • There are no studies designed to answer to pharmacokinetics and pharmacodynamics the question of class effect between that can support either the existence or LHRH analogues, prostate carcinoma, drug LHRH analogues or agonists. Reviews and non-existence of class effect were class effect, androgen deprivation, evidence- meta-analyses have been performed on evaluated. based medicine

INTRODUCTION Evidence-based medicine is defined as: ‘the OBJECTIVES serious, explicit and cautious use of the The term ‘evidence-based medicine’ best evidences available for decision- Using this evidence-based medicine was coined in 1991, and since then this making related to the medical care of each approach, we performed a systematic review assessment method has markedly influenced patient’ [2]. The Cochrane Collaboration, of the literature to determine whether or medical practice. The International Evidence- set up in 1993, is an initiative of paramount not the LHRH analogues (LHRHa) available Based Working Group was set up in the early importance. It focuses on the production, for prescription belong to the same drug 1990s for the diffusion of this new approach, updating and disclosure of systematic class (same family, similar chemical putting forward a paradigmatic change with reviews of the efficacy of medical structure, mechanism of action and several articles published in JAMA [1]. interventions. efficacy).

EVIDENCE-BASED MEDICINE IN THE USE OF LHRH

Roach [15] reported that of the 11 most TABLE 1 Evidence level and grade of recommendation as given by the Scottish Intercollegiate Guidelines important randomized clinical trials (RCTs) Network that have shown improved outcomes when androgen deprivation therapy (ADT) is Levels of evidence added to EBRT, 10 have been performed 1++ High-quality meta-analyses, systematic reviews of randomized controlled clinical trials (RCTs) or with goserelin. He also pointed out that the RCTs with a very low risk of bias. reduction in terms of mortality reported in the 1+ Well-conducted meta-analyses, systematic reviews of RCTs or RCTs with a low risk of bias. 1990s in intermediate-risk and high-risk PCa 1- Meta-analyses, systematic reviews of RCTs or RCTs with a high risk of bias. could largely be the result of the use of 2++ High-quality systematic reviews of case–control or cohort studies. Case–control or cohort LHRHa. studies with a very low risk of bias and a high probability that the relationship is causal. 2+ Well-conducted cohort and case–control studies, with a low risk of bias and a moderate There is less literature support for leuprorelin probability that the relationship is causal. [16,17] and triptorelin [18], and there are 2- Case–control or cohort studies with a high risk of bias and a significant risk that the relationship no studies with buserelin in combination is not causal. with radiation therapy. Randomized studies 3 Non-analytical studies (e.g. case series). regularly use a single LHRHa compound or 4 Expert opinion. give the option to choose between two of them [16,17]. (Level of evidence 1+, Grade of Grades of recommendations recommendation A.) A At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the + target population, or a body of evidence consisting principally of studies rated as 1 , directly INTERMEDIATE-RISK PCA applicable to the target population, and demonstrating overall consistency of results. B A body of evidence including studies rated as 2++, directly applicable to the target population and ++ There is no clear agreement in the demonstrating overall consistency of results. Extrapolated evidence from studies rated as 1 definition of risk groups. The concept of an or 1+. + intermediate-risk group covers a wide set of C A body of evidence including studies rated as 2 , directly applicable to the target population and patients with different risks based on the demonstrating overall consistency of results. Extrapolated evidence from studies rated as 2++. + classification used [19]. An intermediate risk is D Evidence level 3 or 4. Extrapolated evidence from studies rated as 2 . accepted when the patient is at 40–65% 5- year risk of biochemical relapse, or when 15- Taken from reference [3]: SIGN 50: A guideline developers’ handbook (Section 6: Forming guideline year mortality reaches 13%. Today, androgen recommendations), SIGN publication no. 50, 2001. Edinburgh: Scottish Intercollegiate Guidelines deprivation for 6 months in combination with Network. EBRT and dose escalation programmes are both valid options in the treatment of this risk group. MATERIALS AND METHODS these five trials have the longest follow-up of all prospective trials with LHRHa or LHRH Although ADT provides greater biochemical PubMed has been used as the main source agonists. and cause-specific survival control it is of search. We concentrated on analysing not clear whether EBRT dose escalation the original articles, which were the The authors concluded that in patients with minimizes the effect of hormone therapy. source of new studies and references in the locally advanced or localized carcinoma of the For intermediate-risk patients, the 6-month literature. The evidence level and the grade prostate, the addition of goserelin improves androgen blockade scheme of the D’Amico of recommendation have been based on the clinical disease-free survival (CDFS) and study has been adopted as a standard by ‘Scottish Intercollegiate Guidelines Network’ reduces cause-specific mortality after EBRT or many radiation oncologists. The populations [3] (Table 1). RP. These data suggest greater benefit from of this study are men with organ-confined long-term adjuvant treatment than with PCa, treated with EBRT on a randomized basis, shorter androgenic blockade schemes [4]. which includes up to 45 Gy on the pelvis MEDICAL INDICATIONS BASED ON and up to 70 Gy subsequent prostate boost, EVIDENCE Other studies, such as the meta-analysis of with or without neoadjuvant, concomitant or the Radiation Therapy Oncology Group (RTOG) adjuvant androgen block for up to 6 months. LITERATURE SUPPORT [10] and the more recent meta-analysis of the This author showed the benefit in terms of Cochrane Collaboration [11], support these overall survival in the ADT group with a The drug with the greatest literature findings [12]. Both of them point out that follow-up of 6.7 years. However, the facts that support is goserelin. Akaza [4] analysed the best outcome is obtained with adjuvant a significant part of the patients belong to the role of goserelin as an adjuvant to treatment with LHRHa in patients with the high-risk group and that the benefit external beam radiation therapy (EBRT) or intermediate-risk and high-risk prostate of hormonal blockade is limited to patients radical prostatectomy (RP). Five classic trials cancer (PCa). without, or with very low, comorbidity make it are discussed (four with EBRT and one with difficult to interpret [16,20]. Other studies RP) [5–9], analysing 3500 patients [4]. With Other studies support the adjuvant use of have shown similar design inconsistencies a median follow-up from 5.5 to 13.2 years, goserelin with EBRT [13,14] or after RP [9]. [13,14]. (Level of evidence 1-.)

VILAR GONZÁLEZ and MALDONADO PIJUAN

HIGH-RISK PCA and mortality in locally advanced PCa [22]. beneficial. The most recent of these is from Therefore, in high-risk and locally advanced the Cochrane Collaboration ]28], where a 5- There are two systematic reviews and one PCa, EBRT in combination with ADT has year improvement in CSS and OS is reported. meta-analysis that study the efficacy of become the standard therapy. (Level of However, over 10% of the patients in the LHRHa as neoadjuvant and adjuvant evidence 1+, Grade of recommendation A.) maximum androgen blockade group, therapy in locally advanced and localized • The optimum ADT time, which will provide compared with 4% in the group on PCa [11,21]. Another explores the role of the maximum benefit in the control of monotherapy with LHRHa, discontinued the hormonal treatment adjuvant to EBRT in tumours without adding excessive toxicity treatment because of side effects. Therefore locally advanced PCa [22]. No assessment and a negative impact on quality of life, is the net benefit in daily medical practice is of class effect has been obtained from still to be determined [24]. The European questionable. (Level of evidence 1++, Grade of these data. Organization for the Research and Treatment recommendation A.) of Cancer trial EORTC 22961 is helpful in this • The study of the Prostate Cancer Trialists’ The results of neoadjuvant ADT administered respect, indicating that EBRT with 3 years of Collaborative Group [29] reports an improved from 3 to 6 months have shown the ADT is superior to 6 months [18]. (Level of survival with the use of non-steroidal following: evidence 1+, Grade of Recommendation B.) antiandrogens (flutamide and nilutamide) vs cyproterone acetate. This was ratified in other • A significant improvement in terms of ADVANCED OR METASTATIC PCA studies [31,33]. (Level of evidence 1++, Grade of CDFS and biochemical relapse-free survival recommendation A.) when administered before EBRT [11,21]. The • The role of ADT in advanced PCa has also • It must be emphasized that bicalutamide, a RTOG 8610 study also shows an increase been reviewed. A meta-analysis [25] of the non-steroidal antiandrogen, is not analysed in in cause-specific survival (CSS) and, when year 2000 with 24 randomized studies these meta-analyses or in the initial studies of analysed by subgroups, an increase in overall showed no differences between ADT with RTOG. A meta-analysis performed by Klotz survival (OS) in Gleason 2–6 cases is found [6]. LHRHa and orchidectomy in terms of et al. [34] compared the trials of the Prostate There is also an improvement, though only in survival. (Level of evidence 1+, Grade of Cancer Trialists’ Collaborative Group, CSS, in TROG 96.01 [13] (in the ADT branch of recommendation A.) which uses flutamide, with those using 6 months). Furthermore, the data updated by • With regard to the immediate or deferred bicalutamide. The evidence suggests that Crook et al. [14,23] with neoadjuvant ADT of 3 start of ADT, there is a meta-analysis of the bicalutamide, as part of the combination months vs 8 months supports the improved four existing RCTs [26], using an LHRHa in therapy, is very likely to provide a survival CDFS with 8-month neoadjuvant ADT in high- only two of them (referring only to goserelin). advantage over castration. It has been tested risk patients [14,23]. (Level of evidence 1+, The evidence is of limited reliability because in a single study against flutamide with Grade of recommendation A.) of the high likelihood of bias. However, differences favourable to bicalutamide. • Neoadjuvant treatment previous to RP the information available suggests that Though not reaching significance, differences significantly improves pathological variables its immediate or early use for the treatment favourable to bicalutamide were also seen associated with a worse prognosis, but does of advanced PCa reduces disease progression in terms of tolerance and toxicity [35]. A not modify OS or CSS [11,21]. (Level of and progression complications. There may subsequent analysis of this study by Sarosdy evidence 1+, Grade of recommendation A.) be a small but significant improvement in et al. [36] showed that, whereas the results of OS at 10 years. There are no significant maximum androgen blockade compared by The results of adjuvant ADT show: differences in CSS. These findings must the LHRHa used did not show advantages be balanced against the non-negligible for goserelin vs leuprorelin, it was the • There is only one study assessing adjuvant secondary toxicity and the economic costs combination of leuprorelin and flutamide treatment with LHRHa after RP with incurred. More studies are required to better that obtained the worst results. (Level of lymphadenectomy when affected nodes are evaluate efficacy and adverse effects. (Level of evidence 1-.) seen. Messing et al. [9] reported a benefit in Evidence 1-.) OS, CSS and CDFS in the Eastern Cooperative USE IN ADJUVANT TREATMENT TO Oncology Group study ECOG 7887, which is CONCOMITANT USE OF ANTIANDROGENS BRACHYTHERAPY supported by the findings of the long-term study RTOG 8531 [8]. (Level of Evidence 1-.) • The concomitant use of LHRHa with The use of hormone therapy in brachytherapy • However, hormonal adjuvant treatment antiandrogens in adjuvant treatment with is extrapolated from its cytoreducing effect, to EBRT significantly improves biochemical EBRT in high-risk PCa has not been tested in and today there is no evidence supporting its relapse-free survival and CSS at 5 years of RCTs, but an analysis of retrospective data use for improving other variables [37]. (Level follow-up and OS and CDFS beyond 10 years suggests some benefit from their combination of evidence 2+, Grade of recommendation C.) after treatment [11]. A recent meta-analysis [27]. (Level of Evidence 2++, Grade of shows a significant improvement of recommendation B) HORMONAL INTERMITTENCE biochemical relapse-free survival and CDFS, • With regard to the concomitant use of with absolute differences favourable to ADT antiandrogens in combination with LHRHa in Finally, no meta-analyses have been of 10% and 7.7%. Differences are also shown advanced PCa, another five major reviews and performed on the role of hormonal in CSS and OS (5.5% and 4.9%, respectively). It meta-analyses [28–32] confirm that the intermittence, although there are preliminary is concluded that ADT together with EBRT maximum androgen blockade in locally results available from ongoing RCTs [38–40]. significantly reduces clinical recurrences advanced and metastatic disease could be Evidence for the use of LHRHa intermittently

EVIDENCE-BASED MEDICINE IN THE USE OF LHRH

is under study with goserelin and leuprorelin. treated continuously with 11.25 mg/day i.m. are equally effective, though the testosterone Candidate patients for intermittent leuprorelin and 750 mg/day oral flutamide, reduction is faster with leuprorelin. (Level of deprivation are still to be defined. (Level of vs 25 patients treated with 10.8 mg/day evidence 3.) evidence 2+, Grade of recommendation C.) subcutaneous goserelin and 50 mg/day oral bicalutamide for 1 month. Both analogues In a randomized study, Kuhn et al. compared ISSUES TO BE DEFINED were given as injections of a 3-monthly 67 patients with PCa not susceptible to formulation. Testosterone levels were surgery, treated with 3.75 mg i.m. triptorelin The uses of ADT are still to be clarified: measured in the first group and the vs 3.75 mg s.c. leuprorelin, both monthly. in patients with biochemical relapse, on second group respectively 3 months Duration of treatment was 3 months. In concomitant adjuvant and salvage EBRT, and 6 months after the beginning of contrast to the findings of previous studies, and in monotherapy in patients with administration. Testosterone values did not the 2-month testosterone castration level locally advanced PCa. In this last case, show significant differences between the observed was higher with triptorelin: among elderly patients, survival is not two groups, but 10% of the patients in the <1.0 nmol/L in 77% and 48% of the modified [41]. leuprorelin group had a therapeutic escape. patients treated with triptorelin and (Level of evidence 3.) leuprorelin, respectively (P = 0.02). Between 24 and 72 h after injection, 77% (triptorelin) DIRECT COMPARATIVE ANALYSIS AMONG Fujii et al. [43] performed a non-randomized, and 56% (leuprorelin) of the patients had THE DIFFERENT LHRH ANALOGUES retrospective study in 232 Japanese patients, testosterone levels <1.0 nmol/L (P < 0.05). 30% of them with metastatic PCa and the They conclude that triptorelin induces higher In a randomized study, Heyns et al. [42] remainder highly heterogeneous in terms of reductions than leuprorelin [48]. (Level of compared monthly intramuscular agonists treatment and cancer status. Furthermore, evidence 1-.) of triptorelin (3.75 mg) with microspheres 192 patients received steroidal or non- of leuprorelin (7.5 mg) for a total of 9 steroidal antiandrogens concomitantly Finally, the randomized study by Tanaka et al. months in advanced PCa. The testosterone with the use of LHRHa. They were treated [49] compared 3.75 mg s.c. or leuprorelin castration level (<0.5 ng/ml) 29 days after with monthly and quarterly formulations microspheres i.m. vs. 3.6 mg s.c. goserelin the start of treatment showed rates of leuprorelin acetate and goserelin. The in 22 T2–4 Nx Mx PCa patients in a single of 91.2% for triptorelin and 99.3% for doses of leuprorelin were 3.75 mg/day and monthly injection. They assessed the leuprorelin. The cumulative castration 11.25 mg/day, respectively. Castration levels endocrine response differences in the first maintenance percentages were 96.4% and did not show significant differences and 4 weeks. At day 3 the total testosterone 91.2%, respectively. The second endpoint with there were only four escapes during the increase was significantly higher for significant differences was survival. The treatment, two in the group with monthly leuprorelin. Free testosterone was also higher overall survival rates 9 months after the leuprorelin, one in the group with quarterly at days 3 and 7 for leuprorelin treatment. On beginning of treatment were 97% vs 90.5% leuprorelin and the fourth in the set with the other hand, the greatest 28-day total (P = 0.033). It was concluded that triptorelin quarterly goserelin. Testosterone levels in the testosterone reduction favoured goserelin, reduces testosterone levels more slowly, but patients undergoing testosterone escape with a patient undergoing therapeutic maintains them at the reduced level better ranged from 0.51 to 0.65 ng/mL. (Level of escape in the leuprorelin group. The over time, showing a higher 9-month survival. evidence 3.) pharmacokinetics of LH did not show It must be emphasized that the primary aim significant differences, except 28 days after of the study was to address the castration The study by Abbou et al. [47] compared the the start, when suppression was higher and level 29 days after the beginning of the use of 3.75 mg monthly i.m. triptorelin with favourable to goserelin. Both the changes treatment, and not 9-month survival, so 3.75 mg monthly s.c. leuprorelin for a period in testosterone and those in PSA levels these data should be interpreted with of 6 months in 68 patients with metastatic suggest that the pharmacodynamics of caution. Known data, such as the relationship PCa. Nilutamide was used for the prevention each agent may be different, while the between overweight and obesity and the of the LH peak. There were no significant different formulations could affect their risk of testosterone escape [43–45], or the differences in the castration levels obtained at pharmacokinetics. (Level of evidence 1-.) different formulation of leuprorelin in the three time points. The castration rates the USA, Japan or Norway [44,45], also recorded for leuprorelin vs triptorelin 1, 3 and The very few direct comparisons between suggest caution in interpreting these results. 6 months after the start of treatment were LHRHa do not allow definitive conclusions on Moreover, this study showed that similar 100% vs 90%, 97% vs 100%, and 100% vs the class effect [2]. levels of testosterone suppression did not 96%, respectively, again supporting the necessarily lead to a similar clinical efficacy. slower onset of action of triptorelin. This CASTRATION LEVEL AND CLINICAL OUTCOME Furthermore, no deleterious effect is seen finding is more evident if the castration from the lower androgen suppression rate level is reduced from 0.50 ng/mL to The impact of obtaining higher castration seen with triptorelin during the first month. 0.30 ng/mL, with castration rates at levels on survival and other clinical variables (Level of evidence 1-.) 1 month of 86% vs 60%, respectively is unknown. A recent prospective study by (P = 0.02). Furthermore, mean testosterone Morote et al. [50] in advanced patients treated In a retrospective, crossover, non-randomized plasma levels at 1 month were 0.16 ± 0.10 ng/ with ADT has shown that lower testosterone study, Yri et al. [46] compared 40 men mL vs 0.33 ± 0.44 ng/mL, respectively levels are meaningful in terms of androgen- with locally advanced non-metastatic PCa (P = 0.02). They conclude that both treatments independent progression-free survival. The

VILAR GONZÁLEZ and MALDONADO PIJUAN

mean androgen-independent progression- TABLE 2 Comparative effect on castration: randomized controlled trials between luteinizing hormone- free survival in patients undergoing escapes releasing hormone analogues and other means of obtaining androgen deprivation over 0.32 ng/mL was 88 months, significantly lower than the 137 months observed for Analogue Orchidectomy Diethylstilbestrol Ciproterone acetate References those patients without escapes (P < 0.03). Goserelin Yes Yes Yes 53–57 Furthermore, maximum androgen blockade Buserelin Yes Yes – 58–61 with bicalutamide could benefit patients with Triptorelin Yes – – 62 escapes over 0.5 ng/mL. Another study worth Leuprorelin – Yes – 63 considerating is that of Perachino et al. [51], which retrospectively analysed 129 patients with PCa with metastatic bone progression. The multivariate analysis shows a relationship between the testosterone nadir and the CSS Finally, we consider it worth mentioning FIG. 1. Areas of uncertainty and possible increase, and is the first study in this line that pharmacokinetic and pharmacodynamic mechanisms involved in luteinizing hormone- published. Finally, with regard to testosterone issues can distort the presumed class effect. releasing hormone analogue failure. levels and their relationship with survival, Drugs that, in principle, because of their Storage/ some indirect data can be obtained from similar structure and mechanism of action, maintenance the Veterans Administration Cooperative could be considered to be from the same of cold chain Reconstitution Urological Research Group study VAGURG II family, can actually show different showing that the diethylstilboestrol doses pharmacological effects. For instance, used for ADT of 0.2 and 1 mg do not obtain dihydrotestosterone only differs from adequate castration levels in comparison with testosterone in one hydrogen atom [64], a 5-mg dose, but a significant difference is which gives it an affinity 10 times higher seen in terms of OS between the group on for the intracellular androgen receptor and Pharmacokinetics Pharmacodynamics 0.2 mg and that on 5 mg [52]. causes a different effect on gene expression. Furthermore, the different LHRHa are all INDIRECT EVIDENCE OBTAINED decapeptides derived from GnRH, which FROM RCTS differ in the substitution and modification of the amino acid residue in position six.

As it proved impossible to answer the As a result, their half-lives and potencies are - Administration zone - Aseptic cyst - Different efficacy question raised by direct comparative modified. For instance, the relative potency of - Administration route formation - Synergism - Altered metabolism - Antibody - Desensitization or studies, indirect evidence was obtained triptorelin is 100 times higher than that of - Formulation forming resistance from RCTs comparing LHRHa with other GnRH, whereas those of goserelin and of - Dosage reaction - Androgen Receptor - Interval Mutations treatments [2,25]. A class effect is leuprorelin are only 50 times more potent considered to exist between drugs with than GnRH [65]. similar mechanism of action when they generate relative risk reductions having In addition, the type of presentation different analogues and administration routes similar direction and extent. Orchidectomy and location of the intramuscular or [43,68–76]. The reaction can be the result was historically the reference standard subcutaneous implants could significantly of either the analogue itself or the excipient for obtaining ADT. Other options, such as affect their absorption and therapeutic used [69] (Fig. 1). diethylstilboestrol and cyproterone acetate efficacy [43,46,49]. Although, a priori, it might (steroidal antiandrogen), were subsequently be supposed that intramuscular compounds Obesity and overweight have been related to added. The LHRHa were compared with would be better absorbed than subcutaneous higher therapeutic escape rates, particularly respect to the three options without implants, there is no evidence supporting this with the use of leuprorelin acetate, although significant differences in survival being [43]. A study with subcutaneous leuprorelin drug interactions are not ruled out as the found (Table 2 [53–63]). acetate [66] shows that the formation of potential cause [43–45]. Smith [45] reported granuloma is caused by both the foreign- that obese patients show higher levels of free The meta-analysis of Seidenfeld et al. [25] body reaction to the microcapsules and the and total testosterone during ADT compared included 12 trials comparing LHRHa with lipolytic effect described for subcutaneous with men with normal body mass index, orchidectomy and diethylstilboestrol. administration of the LHRHa [67]. despite their lower levels before the start of None of these trials compares the three Incidence would also be related to the treatment. Furthermore, racial factors could analogues directly. The indirect comparison dose administered [66]. The differences in condition efficacy in terms of castration after of the seven studies with goserelin (1137 the method of leuprorelin acetate injection ADT. The effect of analogues is apparently patients), four with buserelin (308) and one can influence the frequency of granuloma higher in Asians than in Caucasians or with leuprorelin (94) shows that the hazard development [66,68–70]. In any case, Africans [43]. ratios for survival of the use of analogues examples have been reported of a relationship separately vs orchidectomy are similar. between inflammatory nodes, granulomas Other situations related to the lack Although these indirect data could suggest a or pseudocysts at the site of administration of efficacy of analogues could be the class effect, the likely bias counsels caution [2]. and the existence of escapes with the use of concurrent existence of hypophyseal

EVIDENCE-BASED MEDICINE IN THE USE OF LHRH

adenomas [77], changes in analogue should decide in his daily practice the level of 7 Bolla M, Collette L, Blank L et al. Long- receptors, presence of antibodies against evidence accepted when prescribing drugs. term results with immediate androgen them, and fast metabolization or absorption suppression and external irradiation in disorders [43,78]. If the class effect between different drugs is patients with locally advanced prostate verified, then on economic grounds the one cancer (an EORTC study): a phase III Even if positive results are obtained in terms with a lower cost should be chosen. Issues randomised trial. Lancet 2002; 360: of similar efficacy of both compounds in related to dosage-form improvements that 103–8 randomized studies, we should also take could involve, or not, additional advantages 8 Pilepich MV, Winter K, Lawton CA into account and compare the differences in for the patient, should be considered in et al. Androgen suppression adjuvant tolerance before accepting the class effect a second plane. We must exercise caution to definitive radiotherapy in prostate [2,79] (Fig. 1). before accepting any claims for novelty carcinoma – long-term results of phase III without a critical review. RTOG 85-31. Int J Radiat Oncol Biol Phys Given the existence of testosterone escapes 2005; 61: 1285–90 with all the above-mentioned mechanisms, The current available evidence is not enough 9 Messing EM, Manola J, Yoo J et al. regular monitoring of testosterone levels to support a presumed drug class effect of Immediate versus deferred androgen is mandatory in our clinical practice to the various analogues in the treatment of deprivation treatment in patients establish the efficacy of action of analogues. carcinoma of the prostate in its different with node positive prostate cancer Furthermore, testosterone levels should clinical situations. after radical prostatectomy and pelvic always be monitored before the diagnosis lymphadenectomy. Lancet Oncol 2006; 7: of resistant castration. CONFLICT OF INTEREST 472–9 10 Roach M 3rd, Lu J, Pilepich MV et al. None declared. 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