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). © 2010 THE AUTHORS 1200 BJU INTERNATIONAL © 2010 BJU INTERNATIONAL | 107, 1200–1208 | doi:10.1111/j.1464-410X.2010.09827.x 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