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, node-positive 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, node-positive prostate cancer?

The role of radiotherapy for node-positive disease is controversial. There are three RCTs containing subgroups of node-positive (primarily biopsy proven) patients that evaluate any effect of adjuvant androgen deprivation when combined with radiotherapy. Two RCTs examined radiotherapy with adjuvant ADT versus radiotherapy with ADT as a possible treatment on progression. The first, RTOG 85-31, used LHRH agonist until progression[1]. The second used a non-steroidal anti-androgen for a minimum of two years.[2] The third RCT examined radiotherapy with concurrent plus adjuvant ADT (orchidectomy prior to radiotherapy) versus radiotherapy with ADT on progression.[3] The largest RCT, RTOG 85-31, was of medium quality for survival whereas the two smaller RCTs were of low quality. In all three trials the analyses for node-positive disease were unplanned subgroup analyses, increasing the risk that the arms may not be balanced for potential risk factors in this subgroup of patients. The largest subgroup with 173 participants was from RTOG 85-31. The Granfors study contained a subgroup of 39 node-positive patients and the Iversen study contained only 14 patients in their node-positive subgroup.[2] Radiotherapy doses were either not described or varied in all studies.

The RTOG 85-31 and Granfors studies provided data for survival, prostate cancer survival and disease progression. The RTOG 85-31 study showed a trend towards improved survival with 6.5 years median follow-up. A multivariate analysis of patients for whom Gleason scores were available and which took into account Gleason score and whether the men had undergone radical prostatectomy found a statistically significant improvement with adjuvant ADT, with a nine-year survival rate of 62% for adjuvant ADT versus 38% for radiotherapy alone. The smaller Granfors trial with a median follow-up of 9.3 years showed a statistically significant survival benefit for immediate orchidectomy with a nine-year survival rate of 50% for immediate orchidectomy therapy versus 13% for radiotherapy alone.[3] Similar results were found for prostate cancer mortality. With longer follow-up to 19 years, this survival benefit was maintained.[4]The Iversen study had reduced rates of clinical or biochemical progression with anti-androgen therapy in their very small subgroup of men.[2]

Isolated biopsy proven node-positive disease represents a relatively small cohort of prostate cancer patients. In these patients there is potential for a major survival benefit with androgen deprivation in addition to radiotherapy. However it is not known whether adding radiotherapy to androgen deprivation for node-positive patients provides any benefit.

Only one of the three RCTs, RTOG 85-31, examined radiotherapy toxicity outcomes for adjuvant ADT–in this trial LHRH agonist therapy–for the node-positive patient subgroup. The authors reported that the incidence of grade 3 and 4 acute and late toxicities was not statistically significantly different.

As long-term adjuvant androgen deprivation as an adjuvant to radiotherapy appears to improve the survival of men with biopsy node-positive prostate cancer, no evidence of increased radiotherapeutic toxicities would have a substantial clinical impact. However, the hormone-associated toxicities that would have an impact on quality of life were not assessed, reducing the clinical impact.

One trial reports no difference in grade 3 and 4 toxicities with LHRH agonist treatment after radiotherapy. Other known toxicities of hormonal therapy were not reported. [1]

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Evidence summary and recommendations

Evidence summary Level References
Both of the two larger RCT subgroup analyses for biopsy proven node-positive disease that were examined showed that castration, either LHRH agonist until progression or orchidectomy, resulted in significant overall and cancer-specific survival benefits when combined with radiotherapy. II [1], [2], [3]
Evidence-based recommendationQuestion mark transparent.png Grade
If radical radiotherapy is given to patients with node-positive disease it is reasonable to offer long-term androgen deprivation in addition to radiotherapy.
D


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References

  1. 1.0 1.1 1.2 Lawton CA, Winter K, Grignon D, Pilepich MV. Androgen suppression plus radiation versus radiation alone for patients with stage D1/pathologic node-positive adenocarcinoma of the prostate: updated results based on national prospective randomized trial Radiation Therapy Oncology Group 85-31. J Clin Oncol 2005 Feb 1;23(4):800-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15681524.
  2. 2.0 2.1 2.2 2.3 Iversen P, Wirth MP, See WA, McLeod DG, Klimberg I, et al. Is the efficacy of hormonal therapy affected by lymph node status? data from the bicalutamide (Casodex) Early Prostate Cancer program. Casodex Early Prostate Cancer Trialists' Group. Urology 2004 May;63(5):928-33 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15134983.
  3. 3.0 3.1 3.2 Granfors T, Modig H, Damber JE, Tomic R. Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study. J Urol 1998 Jun;159(6):2030-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9598512.
  4. Granfors T, Modig H, Damber JE, Tomic R. Long-term followup of a randomized study of locally advanced prostate cancer treated with combined orchiectomy and external radiotherapy versus radiotherapy alone. J Urol 2006 Aug;176(2):544-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16813885.

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Appendices