What should be done for patients with locally advanced disease who are not suitable candidates for surgery or radiotherapy – primary androgen deprivation at diagnosis or wait until clinical progression (localized or metastatic) - Timing?

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What should be done for patients with locally advanced disease who are not suitable candidates for surgery or radiotherapy – primary androgen deprivation at diagnosis or wait until clinical progression (localized or metastatic) - Timing?

Early versus delayed androgen deprivation therapy

Some patients may not be suitable for definitive local therapy because of co-morbidities or advanced age. Data are emerging to provide guidance on the timing of ADT for patients with locally advanced disease and for those with locally advanced disease who decline surgery or radiotherapy. The question for these patients with no evidence of metastases on imaging is whether to start ADT immediately or wait until clinical progression (localised or metastatic).

There is an extensive amount of data addressing this issue, covering the period from the 1970s to 2006. This complicates the analysis because of:

  • issues of stage migration and stage detection with pre bone scan and pre PSA era incorporated with studies involving patients who are more accurately staged in modern era
  • different treatments from different eras included oestrogens, orchidectomy, anti-androgen monotherapy and luteinising hormone releasing hormone (LHRH) agonist therapy
  • heterogeneity of study populations within studies and data findings based on subgroup analyses
  • lack of adherence in some studies to study treatment plan (MRC study some controls did not receive treatment on progression)
  • the more recent emphasis on the Gleason grade and PSA, doubling time to identify patients with more aggressive disease.

The body of data supporting androgen deprivation appears to be consistent in that immediate treatment shows a disease-specific survival advantage[1], [2] and on occasion an overall survival advantage[2] for men with locally advanced disease. However, the overall impression suggests that if there is a benefit, it is modest. Findings from the two studies cited above were based on subgroup analyses of RCTs that included men with locally advanced disease as well as men with metastatic disease. The VACURG-1[1] study may have included a significant number of men with more advanced disease (asymptomatic metastases) as bone scans were not used for staging. Data would suggest that immediate treatment versus waiting until symptomatic progression is evident does not provide a survival advantage (see chapter 5 Overt metastatic disease and/or loco-regional progressive disease). As a result, any survival benefit for men with truly locally advanced disease only may have been diluted. On the other hand, the overall survival advantage (p=0.02 log rank test) in MRC study of 503 patients with non-metastatic disease was confounded by a significant proportion of the patients not receiving ADT in the deferred arm.[2]

The most informative data in the modern era for the timing of castration therapies comes from two RCTs with similar results. The first study[3] compared immediate versus delayed orchidectomy or LHRH agonists for patients with microscopic (histological or cytological) lymph node (N1–3) positive disease with pathologically confirmed disease who did not undergo a prostatectomy and/or full lymphadenectomy. The study accrued 234 patients who were considered suitable for surgery and prepared for prostatectomy but the prostatectomy was not performed because of lymph node involvement. With a median follow-up of 13 years, there was a hazard ratio of 1.22 (95% CI=0.92 to 1.62) suggesting a possible benefit for immediate therapy.[4] This study was underpowered and did not include men with locally advanced disease considered unsuitable for definitive local therapy.

The second study, a major EORTC study published immediately after 1 April 2006, accrued patients who were not candidates for local definitive treatments due to co-morbid illnesses age and/or advanced local tumour stage, or were refused for local therapy.[5] At a median follow-up of 7.8 years, 541 of 985 patients had died, 193 from prostate cancer and 183 from cardiovascular disease. The overall survival benefit was modest, with a hazard ratio adjusted for a number of factors, including tumour stage, of 1.29 (95% CI=1.09 to 1.53) favouring immediate treatment, seemingly due to fewer deaths from non-prostatic cancer causes. This study was limited for the purpose of this review by the fact that about 50% of the patients did not have locally advanced disease according to the operating definition.

The anti-androgen monotherapy data from a subgroup analysis of a pooled analysis of three RCTs trended towards a survival benefit with anti-androgen therapy when compared with watchful waiting (hazard ratio = 0.81 (0.66 – 1.01) p=0.06) consistent with a treatment effect controlling disease. However this study was potentially confounded by unclear treatment at progression, and use of a class of agent that is less effective as monotherapy in metastatic disease[6] Any benefit (if present) however, has limited clinical applicability to Australia as these drugs are not approved on the PBS as monotherapy.Overall the data suggest there may be a modest benefit for immediate or primary ADT for patients with locally advanced disease deemed not suitable for definitive local therapy. However, decisionshave to be weighed against the impact of ADT on quality of life. This issue is relevant as there is a large number of men with prostate cancer who are not suitable for definitive local therapy and as these studies reflect, this is often a disease found in elderly men.

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Evidence summary and recommendations

Evidence summary Level References
For locally advanced disease the body of data for androgen suppressive therapy (medical or surgical) appears consistent in that immediate treatment shows a disease-specific survival advantage and on occasion an overall survival advantage. However, the overall impression suggests that if there is a benefit, it is modest. II [1], [2], [3], [6], [7]
Evidence-based recommendationQuestion mark transparent.png Grade
No strong recommendation can be made for the use of androgen deprivation therapy in locally advanced disease. However, there may be a modest benefit for immediate or primary androgen deprivation therapy for patients with locally advanced disease deemed not suitable for definitive local therapy. However, this has to be weighed against the impact of androgen deprivation therapy on quality of life.
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References

  1. 1.0 1.1 1.2 Jordan WP Jr, Blackard CE, Byar DP. Reconsideration of orchiectomy in the treatment of advanced prostatic carcinoma. South Med J 1977 Dec;70(12):1411-3 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/594790.
  2. 2.0 2.1 2.2 2.3 The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. Br J Urol 1997 Feb;79(2):235-46 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9052476.
  3. 3.0 3.1 Schröder FH, Kurth KH, Fosså SD, Hoekstra W, Karthaus PP, et al. Early versus delayed endocrine treatment of pN1-3 M0 prostate cancer without local treatment of the primary tumor: results of European Organisation for the Research and Treatment of Cancer 30846--a phase III study. J Urol 2004 Sep;172(3):923-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15310999.
  4. Schröder FH, Kurth KH, Fossa SD, Hoekstra W, Karthaus PP, De Prijck L, et al. Early versus delayed endocrine treatment of T2-T3 pN1-3 M0 prostate cancer without local treatment of the primary tumour: final results of European Organisation for the Research and Treatment of Cancer protocol 30846 after 13 years of follow-up (a randomised controlled trial). Eur Urol 2009 Jan;55(1):14-22 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18823693.
  5. Studer UE, Whelan P, Albrecht W, Casselman J, de Reijke T, Hauri D, et al. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) Trial 30891. J Clin Oncol 2006 Apr 20;24(12):1868-76 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16622261.
  6. 6.0 6.1 McLeod DG, Iversen P, See WA, Morris T, Armstrong J, et al. Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 2006 Feb;97(2):247-54 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16430622.
  7. Byar DP. Proceedings: The Veterans Administration Cooperative Urological Research Group's studies of cancer of the prostate. Cancer 1973 Nov;32(5):1126-30 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/4585929.

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Appendices