What is the efficacy of external beam radiotherapy techniques for locally advanced disease?

From Cancer Guidelines Wiki

What is the efficacy of external beam radiotherapy techniques for locally advanced disease?

Definitive external beam radiotherapy techniques for locally advanced disease

There are nine randomised controlled trials comparing various definitive external beam radiotherapy techniques that include men with locally advanced disease. These studies investigate:

  • limited versus extended field radiotherapy (three trials)
  • various dose regimens (four trials), and
  • conformal versus conventional techniques (two trials).

Limited radiation fields refer to treating the prostate alone with or without the seminal vesicles, whereas extended field radiotherapy includes treating the whole pelvis and in some cases the paraaortic nodes. The dose regimen trials have used various techniques to explore dose-escalated radiotherapy to between 74 and 80Gy compared with the more traditional doses between 64 and 70Gy. 3D conformal radiotherapy refers to the practice of conforming the shape of radiation fields to the prostate (based on CT imaging) in order to reduce dose to critical surrounding tissues.

The studies are variously limited by lack of stratification for types of locally advanced disease, old definitions of locally advanced disease, small numbers, lack of standardisation of endocrine therapy, differences in nodal volumes irradiated, relatively short follow-up, lack of blinding and lack of quality-of-life endpoints. Efficacy outcomes for locally advanced disease are restricted to subgroup analyses and the only toxicity data reported is for entire cohorts of men with T1–4 disease. Overall there are low volumes of good-quality evidence available.

Notwithstanding the above limitations, the two subgroup analyses comparing limited with extended field radiotherapy and examining efficacy outcomes show no differences in efficacy in terms of survival, progression-free survival or metastases.[1][2][3] In the entire cohorts of men with T1–4 disease there are no consistent differences in reported toxicity.[1][2][3][4][5][6] Because of this, it is common practice in Australia to treat limited fields only. However treating the whole pelvis can be justified in selected high-risk patients as at least two of the randomised trials demonstrating the benefit of combining adjuvant ADT with radiotherapy have incorporated whole pelvis radiotherapy.[7][8]

Studies of dose escalation consistently show improved efficacy in terms of freedom from biochemical or clinical failure for high-risk patients[9] [10] including a subgroup of 60 T3 patients.[11] This trend was statistically significant in two of the studies.[10] [11]Late rectal toxicity appears to be worse with higher doses.[10][12][13][14][15][16][17] For other endpoints there appear to be inconsistent differences.[10] [11]Late rectal toxicity appears to be worse with higher doses.[10][12][13][14][15][16][17][18] There is a potential for dose escalation to have a significant clinical impact by improving efficacy. Further evidence is required in this subgroup of patients.

Studies comparing conformal with conventional radiotherapy are not powered for differences inefficacy. There are inconsistent differences in acute and late toxicities, although the differences that exist all favour conformal radiotherapy.[19][20][21] There is potential to have a significant clinical impact by reducing toxicity. Further evidence is required in this subgroup of patients.

Evolution in technologies has led to refinements in 3D conformal therapies with the introduction of Intensity modulated and image guided radiation treatments ( IMRT and IGRT) which allow for better targeting of the prostate and shielding of critical surrounding tissues. These techniques facilitate improved delivery of dose escalated external beam radiation therapy. The results of these newer methods of delivery of treatment will no doubt become available in due course. Furthermore, the role of shortened courses of 3D conformal radiation therapy (hypo-fractionated regimens with biologically equivalent doses) compared with the traditional long courses of conventionally fractionated 3D conformal treatments are also currently being investigated in randomised studies.

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Evidence summary and recommendations

Evidence summary Level References
There is no evidence to support the routine use of extended field radiotherapy for locally advanced prostate cancer. The role of whole pelvis radiotherapy has yet to be defined.

There is some evidence to support the increased efficacy for doseescalated external beam radiotherapy for biochemical and clinical relapse. These data have not yet translated into improved survival or a reduction in distant disease-free survival. There is some evidence that dose-escalation increases toxicity, however, the impact on quality of life is yet to be determined. It is uncertain whether an benefits of dose escalation can be generalised to patients receiving neoadjuvant and/or adjuvant endocrine therapy. There is evidence that conformal radiotherapy decreases toxicity compared with conventional radiotherapy

II [1], [2], [3], [5], [11], [12], [13], [14], [15], [16], [18], [19], [20], [21], [22]
Evidence-based recommendationQuestion mark transparent.png Grade
When radiation therapy alone is used, limited field radiotherapy has similar efficacy and has less toxicity than whole pelvis and therefore is recommended. The role of whole pelvis radiation is yet to be defined.

Consideration should be given to dose escalation (74Gy or higher) if it can be delivered safely.

Patients with locally advanced prostate cancer should receive 3D conformal radiation to minimise toxicity.

C


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References

  1. 1.0 1.1 1.2 Pilepich MV, Krall JM, Johnson RJ, Sause WT, Perez CA, Zinninger M, et al. Extended field (periaortic) irradiation in carcinoma of the prostate--analysis of RTOG 75-06. Int J Radiat Oncol Biol Phys 1986 Mar;12(3):345-51 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3514555.
  2. 2.0 2.1 2.2 Pilepich MV, Krall JM, Sause WT, Johnson RJ, Russ HH, Hanks GE, et al. Correlation of radiotherapeutic parameters and treatment related morbidity in carcinoma of the prostate--analysis of RTOG study 75-06. Int J Radiat Oncol Biol Phys 1987 Mar;13(3):351-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3494005.
  3. 3.0 3.1 3.2 Roach M 3rd, DeSilvio M, Lawton C, Uhl V, Machtay M, et al. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 2003 May 15;21(10):1904-11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12743142.
  4. Lawton CA, DeSilvio M, Roach M 3rd, Uhl V, Kirsch R, Seider M, et al. An update of the phase III trial comparing whole pelvic to prostate only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions. Int J Radiat Oncol Biol Phys 2007 Nov 1;69(3):646-55 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17531401.
  5. 5.0 5.1 Pommier P, Perol D, Lagrange J, Richaud P, Brune D, Le Prise E et al. Does pelvis and prostate radiation therapy compared to prostate radiation therapy alone improve survival in patients with non metastatic prostate carcinoma? Preliminary results of the prospective randomized GETUG 01 trial. International Journal of Radiation Oncology Biology Physics 2005.
  6. Pommier P, Chabaud S, Lagrange JL, Richaud P, Lesaunier F, Le Prise E, et al. Is there a role for pelvic irradiation in localized prostate adenocarcinoma? Preliminary results of GETUG-01. J Clin Oncol 2007 Dec 1;25(34):5366-73 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18048817.
  7. 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. 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.
  9. Peeters ST, Heemsbergen WD, Koper PC, van Putten WL, Slot A, Dielwart MF, et al. Dose-response in radiotherapy for localized prostate cancer: results of the Dutch multicenter randomized phase III trial comparing 68 Gy of radiotherapy with 78 Gy. J Clin Oncol 2006 May 1;24(13):1990-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16648499.
  10. 10.0 10.1 10.2 10.3 10.4 Dearnaley DP, Sydes MR, Graham JD, Aird EG, Bottomley D, et al. Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. Lancet Oncol 2007 Jun;8(6):475-87 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17482880.
  11. 11.0 11.1 11.2 11.3 Pollack A, Zagars GK, Smith LG, Lee JJ, von Eschenbach AC, Antolak JA, et al. Preliminary results of a randomized radiotherapy dose-escalation study comparing 70 Gy with 78 Gy for prostate cancer. J Clin Oncol 2000 Dec 1;18(23):3904-11 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11099319.
  12. 12.0 12.1 12.2 Dearnaley DP, Hall E, Lawrence D, Huddart RA, Eeles R, Nutting CM, et al. Phase III pilot study of dose escalation using conformal radiotherapy in prostate cancer: PSA control and side effects. Br J Cancer 2005 Feb 14;92(3):488-98 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15685244.
  13. 13.0 13.1 13.2 Peeters ST, Heemsbergen WD, van Putten WL, Slot A, Tabak H, Mens JW, et al. Acute and late complications after radiotherapy for prostate cancer: results of a multicenter randomized trial comparing 68 Gy to 78 Gy. Int J Radiat Oncol Biol Phys 2005 Mar 15;61(4):1019-34 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15752881.
  14. 14.0 14.1 14.2 Pollack A, Zagars GK, Starkschall G, Antolak JA, Lee JJ, Huang E, et al. Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002 Aug 1;53(5):1097-105 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12128107.
  15. 15.0 15.1 15.2 Storey MR, Pollack A, Zagars G, Smith L, Antolak J, Rosen I. Complications from radiotherapy dose escalation in prostate cancer: preliminary results of a randomized trial. Int J Radiat Oncol Biol Phys 2000 Oct 1;48(3):635-42 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11020558.
  16. 16.0 16.1 16.2 Little DJ, Kuban DA, Levy LB, Zagars GK, Pollack A. Quality-of-life questionnaire results 2 and 3 years after radiotherapy for prostate cancer in a randomized dose-escalation study. Urology 2003 Oct;62(4):707-13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14550448.
  17. 17.0 17.1 Kuban DA, Tucker SL, Dong L, Starkschall G, Huang EH, Cheung MR, et al. Long-term results of the M. D. Anderson randomized dose-escalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2008 Jan 1;70(1):67-74 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17765406.
  18. 18.0 18.1 Beckendorf V, Guérif S, Le Prisé E, Cosset JM, Lefloch O, Chauvet B, et al. The GETUG 70 Gy vs. 80 Gy randomized trial for localized prostate cancer: feasibility and acute toxicity. Int J Radiat Oncol Biol Phys 2004 Nov 15;60(4):1056-65 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15519775.
  19. 19.0 19.1 Koper PC, Stroom JC, van Putten WL, Korevaar GA, Heijmen BJ, Wijnmaalen A, et al. Acute morbidity reduction using 3DCRT for prostate carcinoma: a randomized study. Int J Radiat Oncol Biol Phys 1999 Mar 1;43(4):727-34 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10098427.
  20. 20.0 20.1 Koper PC, Jansen P, van Putten W, van Os M, Wijnmaalen AJ, Lebesque JV, et al. Gastro-intestinal and genito-urinary morbidity after 3D conformal radiotherapy of prostate cancer: observations of a randomized trial. Radiother Oncol 2004 Oct;73(1):1-9 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15465140.
  21. 21.0 21.1 Dearnaley DP, Khoo VS, Norman AR, Meyer L, Nahum A, Tait D, et al. Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial. Lancet 1999 Jan 23;353(9149):267-72 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9929018.
  22. Kuban D, Pollack A, Huang E, Levy L, Dong L, Starkschall G, et al. Hazards of dose escalation in prostate cancer radiotherapy. Int J Radiat Oncol Biol Phys 2003 Dec 1;57(5):1260-8 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14630260.

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Appendices