Is there any survival advantage for androgen blockade (androgen ablation, deprivation) when used as first line therapy in the adjuvant or neoadjuvant setting with radiotherapy for locally advanced prostate cancer?

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Is there any survival advantage for androgen blockade (androgen ablation, deprivation) when used as first line therapy in the adjuvant or neoadjuvant setting with radiotherapy for locally advanced prostate cancer?

For the purpose of this section we have considered the evidence in terms of short-term (six months or less) and long-term (more than six months) androgen blockade.

Long-term androgen deprivation

Four randomised controlled trials[1] [2][3][4]and two meta-analyses[5][6] fulfilled the eligibility criteria for inclusion in this review. The control arm in these trials was radiotherapy alone. Androgen deprivation consisted of oestrogen[3], LHRH agonist[7][4] and a non-steroidal anti-androgen.[1] Duration of ADT ranged from two years to indefinitely and was commenced with radiotherapy[4] or at completion of radiotherapy. The radiotherapy dose to the prostate in three of the trials ranged from 65 to 70 Gy. No data regarding radiotherapy were given in the fourth trial.[1] In two of the trials, pelvic lymph nodes were treated.[7][4][2]/ In all trials the endpoint of overall survival was examined.

These studies showed a statistically significant improvement in overall survival with the exception of the study by Zagars[3], which was a low-quality study using long-term oestrogens. While improved biochemical disease-free survival was also observed, it should be noted that in two of the trials[7][2][3] indefinite ADT was recommended. Biochemical failure in the context of indefinite androgen deprivation most likely represents castrate-resistant disease and these results should therefore be interpreted with caution.

Short-term androgen deprivation

Only one RCT, Trans Tasman Radiation Oncology Group (TROG) 96-01, fulfilled the eligibility criteria for inclusion in this review.[8] This was a three-arm study comparing external beam radiotherapy (EBRT) alone versus three months of hormones plus EBRT (commenced two months prior to radiotherapy) versus six months of hormones plus EBRT (commenced five months prior to radiotherapy). ADT consisted of an LHRH agonist (goserelin) and a non-steroidal anti-androgen (flutamide). The radiotherapy dose was 66Gy in 33 fractions, which is lower than the current standard dose used in Australia (typically 74Gy). Subgroup analysis of patients with T3–4 disease and patients with PSA>20 was only available for the comparison of EBRT alone versus six months of hormones plus EBRT, with disease-free survival and prostate-cancer-specific survival reported. This demonstrated a statistically significant improvement in disease-free survival with the addition of six months of hormones, but not in prostate-cancer-specific survival.

It should be noted that radiation doses were lower than current standard doses used in Australia and target volumes varied, with several trials treating pelvic lymph nodes. There are no RCTs addressing the use of ADT in conjunction with brachytherapy and it remains unclear as to whether ADT provides a benefit in the era of higher-dose radiotherapy. On a final note, the Radiation Therapy Oncology Group (RTOG) 86–10[9] was not considered in this review as it did not meet inclusion criteria for survival outcomes.

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Evidence summary and recommendations

Evidence summary Level References
Multiple randomised trials and two meta-analyses show that longterm androgen deprivation in conjunction with radiation improves overall survival.

Six months of combined androgen deprivation commencing five months prior to radiotherapy improves disease-free survival. The optimal timing and duration of adjuvant androgen deprivation remains to be defined.

I, II [5], [7], [8], [1], [4], [2], [3], [6]
Evidence-based recommendationQuestion mark transparent.png Grade
It is recommended that patients with locally advanced prostate cancer who are receiving

treatment with radical radiotherapy receive long-term androgen deprivation (at least two years).

B
Evidence-based recommendationQuestion mark transparent.png Grade
Short-term neoadjuvant androgen deprivation therapy can be considered for patients with locally advanced prostate cancer.
C
Evidence-based recommendationQuestion mark transparent.png Grade
The optimal sequencing and duration of androgen deprivation in relation to radiotherapy is yet to be defined.
C


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References

  1. 1.0 1.1 1.2 1.3 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.
  2. 2.0 2.1 2.2 2.3 Horwitz EM, Winter K, Hanks GE, Lawton CA, Russell AH, Machtay M. Subset analysis of RTOG 85-31 and 86-10 indicates an advantage for long-term vs. short-term adjuvant hormones for patients with locally advanced nonmetastatic prostate cancer treated with radiation therapy. Int J Radiat Oncol Biol Phys 2001 Mar 15;49(4):947-56 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11240235.
  3. 3.0 3.1 3.2 3.3 3.4 Zagars GK, Johnson DE, von Eschenbach AC, Hussey DH. Adjuvant estrogen following radiation therapy for stage C adenocarcinoma of the prostate: long-term results of a prospective randomized study. Int J Radiat Oncol Biol Phys 1988 Jun;14(6):1085-91 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3133327.
  4. 4.0 4.1 4.2 4.3 4.4 Bolla M, Collette L, Blank L, Warde P, Dubois JB, Mirimanoff RO, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002 Jul 13;360(9327):103-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12126818.
  5. 5.0 5.1 Seidenfeld J, Samson DJ, Aronson N, Albertson PC, Bayoumi AM, Bennett C, et al. Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostate cancer. Evid Rep Technol Assess (Summ) 1999 May;(4):i-x, 1-246, I1-36, passim Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11098244.
  6. 6.0 6.1 Kumar S, Shelley M, Harrison C, Coles B, Wilt TJ, Mason MD. Neo-adjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer. Cochrane Database Syst Rev 2006 Oct 18;(4):CD006019 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17054269.
  7. 7.0 7.1 7.2 7.3 Pilepich MV, Winter K, Lawton CA, Krisch RE, Wolkov HB, Movsas B, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma--long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005 Apr 1;61(5):1285-90 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15817329.
  8. 8.0 8.1 Denham JW, Steigler A, Lamb DS, Joseph D, Mameghan H, et al. Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial. Trans-Tasman Radiation Oncology Group,. Lancet Oncol 2005 Nov;6(11):841-50 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16257791.
  9. Pilepich MV, Winter K, John MJ, Mesic JB, Sause W, Rubin P, et al. Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001 Aug 1;50(5):1243-52 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11483335.

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Appendices