Are cumulative treatment toxicities different when androgen blockade (androgen ablation, deprivation) is used as first line therapy in the adjuvant or neoadjuvant setting with radiotherapy for locally advanced prostate cancer in locally advanced disease?

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Are cumulative treatment toxicities different when androgen blockade (androgen ablation, deprivation) is used as first line therapy in the adjuvant or neoadjuvant setting with radiotherapy for locally advanced prostate cancer in locally advanced disease?

The effect of long-term androgen deprivation on radiotherapy toxicities

Two RCTs assessing long-term androgen deprivation therapy in addition to radiotherapy report radiotherapy toxicity outcomes. The first trial is a comparison of XRT alone versus radiotherapy with three years of LHRH agonist.[1] This trial used whole pelvis radiotherapy. The second trial is a comparison of radiotherapy alone versus radiotherapy with two to five years of a non–steroidal anti– androgen, bicalutamide.[2] No details regarding radiotherapy are available for this trial.

An increase in urinary incontinence (16 versus 29%, p=0.002) with the addition of androgen deprivation therapy was reported in one trial.[1]No increase in acute urinary or bowel toxicity or other late toxicity was reported in this trial. While there was no apparent increase in urinary or bowel toxicity in the second trial[2]they were not assessed for statistical significance.

A recent update of RTOG 85-31 which compared radiotherapy alone with radiotherapy plus indefinite adjuvant androgen blockade also reported no statistically significantly difference in RTOG grade 3–4 genitourinary or gastrointestinal toxicities.[3]

The effect of short-term androgen deprivation on radiotherapy toxicities

Three RCTs assessing short-term ADT in addition to radiotherapy report radiotherapy toxicity outcomes. The first trial, TROG 96-01, is a comparison of radiotherapy alone versus three months and six months of neoadjuvant ADT.[4] [5] The second trial, RTOG 86-01, is a comparison of radiotherapy alone versus radiotherapy with three months of ADT.[6][7] Whole pelvis radiotherapy was used. The third trial is a comparison of radiotherapy alone versus radiotherapy with six months of ADT.[8] In all trials ADT consisted of an LHRH agonist and a non-steroidal anti-androgen, flutamide. All trials were consistent, with no increase in acute or late urinary or bowel toxicity reported with the addition of androgen blockade.

A fourth trial, RTOG 83-07, compared Megestrol versus Diethylstilbestrol.[9] These drugs would not be routinely used as first-line therapy and as such this trial was not considered further.

The effect of short-term versus long-term androgen deprivation on radiotherapy toxicities

One RCT, RTOG 92-02,[10][11] compared short-term with long-term androgen deprivation (four months neoadjuvant plus concurrent LHRH agonist and non-steroidal anti-androgen, flutamide, with or without two years of adjuvant LHRH agonist). This trial used whole pelvis radiotherapy. A statistically significant increase in late RTOG gastrointestinal toxicity grade 3–5 was reported with long-term ADT although absolute rates were low (3 versus 1%, p=0.04) and grade 4 or 5 toxicities were less than 1%.[10] Accounting for differences in reporting of toxicity the evidence suggests that there is no significant increase in radiotherapy toxicity with the addition of ADT. It should be noted that sexual function is inadequately assessed in these studies. Only one trial has reported an increase in late impotence with six months of androgen deprivation.[8]

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Evidence summary and recommendations

Evidence summary Level References
There does not appear to be any difference in radiotherapy toxicities (urinary and gastrointestinal) with the addition of androgen deprivation therapy to radiotherapy, although it is acknowledged that sexual function has been inadequately assessed in these studies. II [4], [5], [6], [8], [7], [1], [2], [10], [11]
Evidence-based recommendationQuestion mark transparent.png Grade
Androgen deprivation therapy can be used in combination with radiotherapy without additional radiotherapy toxicities (urinary and gastrointestinal). Effect on sexual functioning has not been defined.
C


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References

  1. 1.0 1.1 1.2 Bolla M, Gonzalez D, Warde P, Dubois JB, Mirimanoff RO, Storme G, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997 Jul 31;337(5):295-300 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9233866.
  2. 2.0 2.1 2.2 Tyrrell CJ, Payne H, See WA, McLeod DG, Wirth MP, et al. Bicalutamide ('Casodex') 150 mg as adjuvant to radiotherapy in patients with localised or locally advanced prostate cancer: results from the randomised Early Prostate Cancer Programme'Casodex' Early Prostate Cancer Trialists Group. Radiother Oncol 2005 Jul;76(1):4-10 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16145740.
  3. Lawton CA, Bae K, Pilepich M, Hanks G, Shipley W. Long-term treatment sequelae after external beam irradiation with or without hormonal manipulation for adenocarcinoma of the prostate: analysis of radiation therapy oncology group studies 85-31, 86-10, and 92-02. Int J Radiat Oncol Biol Phys 2008 Feb 1;70(2):437-41 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17881145.
  4. 4.0 4.1 Lamb DS, Denham JW, Mameghan H, Joseph D, Turner S, Matthews J, et al. Acceptability of short term neo-adjuvant androgen deprivation in patients with locally advanced prostate cancer. Radiother Oncol 2003 Sep;68(3):255-67 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/13129633.
  5. 5.0 5.1 Christie D, Denham J, Steigler A, Lamb D, Turner S, Mameghan H, et al. Delayed rectal and urinary symptomatology in patients treated for prostate cancer by radiotherapy with or without short term neo-adjuvant androgen deprivation. Radiother Oncol 2005 Nov;77(2):117-25 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16271786.
  6. 6.0 6.1 Pilepich MV, Krall JM, al-Sarraf M, John MJ, Doggett RL, Sause WT, et al. Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology 1995 Apr;45(4):616-23 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7716842.
  7. 7.0 7.1 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.
  8. 8.0 8.1 8.2 D'Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 2004 Aug 18;292(7):821-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15315996.
  9. Pilepich MV, Buzydlowski JW, John MJ, Rubin P, McGowan DG, Marcial VA. Phase II trial of hormonal cytoreduction with megestrol and diethylstilbestrol in conjunction with radiotherapy for carcinoma of the prostate: outcome results of RTOG 83-07. Int J Radiat Oncol Biol Phys 1995 Apr 30;32(1):175-80 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7721614.
  10. 10.0 10.1 10.2 Hanks GE, Pajak TF, Porter A, Grignon D, Brereton H, et al. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol 2003 Nov 1;21(21):3972-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14581419.
  11. 11.0 11.1 Asbell SO, Leon SA, Tester WJ, Brereton HD, Ago CT, Rotman M. Development of anemia and recovery in prostate cancer patients treated with combined androgen blockade and radiotherapy. Prostate 1996 Oct;29(4):243-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8876707.

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Appendices