81Radiotherapy dose fractionation Third edition
Background
Early prostate cancer is being diagnosed more frequently because of prostate-specic
antigen (PSA) screening. This change in natural history poses new management
opportunities and external-beam radiotherapy (EBRT) is only one of several options, which
include active surveillance and monitoring, radical surgery and brachytherapy.
Hormonal therapy and radiation dose
There is Grade A evidence in favour of neoadjuvant or adjuvant androgen deprivation
therapy (ADT) for patients with intermediate or high-risk (PSA >10 or Gleason score >7 or
T2C–T3) prostate cancer treated with radical radiotherapy, although with the likelihood of
signicant toxicity reducing quality of life.
1
A systematic review of 14 randomised phase III
clinical trials showed benet which increases as the risk factors of stage, PSA and Gleason
score increase.
2
The National Institute for Health and Care Excellence (NICE) guidelines
recommend six months of ADT for intermediate-risk patients, which may be extended for
up to three years in high-risk localised prostate cancer.
3
There are now ve randomised dose escalation studies which have demonstrated superior
biochemical relapse-free survival (bRFS) with doses from 74–80 Gray (Gy) compared to
lower doses. As yet, however, this has not translated into an overall survival advantage.
4–8
Fractionation
A full discussion of the radiobiology of prostate cancer is outside of the remit of this
guideline. There is consistent evidence from large retrospective series to support the
hypothesis that prostate cancer has a low αβ ratio.
9,10
Hypofractionation, using fraction sizes
>2 Gy per day, may therefore be radiobiologically advantageous.
Conventional fractionation (doses-per-fraction in the range 1.8–2 Gy)
The results of conventional fractionation have been comprehensively reviewed and
reported. Dose escalation has been shown to improve bRFS in randomised controlled trials
(RCT) (64 Gy versus 74 Gy , 68 Gy versus 78 Gy, 70 Gy versus 78 Gy, 70.2 Gy versus 79.2 Gy)
as well as meta-analysis.
4–8,11
Unfortunately, this has not translated into improved overall
survival as yet.
There is evidence (Grade B) that doses beyond 80 Gy can now be delivered safely with
image-guided intensity-modulated radiotherapy (IMRT).
1
There are no reported randomised
trials of higher levels of dose escalation, but results from the Memorial Sloan Kettering
Cancer Center have shown that the late grade II gastrointestinal toxicity rates of patients
treated to 86.4 Gy in fraction sizes of 1.8 Gy was 3%, with <1% developing late grade III
gastrointestinal toxicity.
12
Analysis of outcomes from this series showed that the ten-year
failure free survival (bNED) was signicantly improved by dose escalation: 84% (>75.6 Gy)
versus 70% for low-risk disease (p=0.04), 76% (>81 Gy) versus 57% for intermediate-risk
disease (p=0.0001) and 55% (>81 Gy) versus 41% for high-risk patients (p=0.0001).
13
In a
multivariate analysis including the use of six-months ADT, a dose >81 Gy (p=0.027) and ADT
(p=0.052) were found to be predictive factors for distant metastasis-free survival, but not
overall survival.
11.
Prostate cancer
82Radiotherapy dose fractionation Third edition
Hypofractionation (doses of 2.5 Gy per fraction and above)
Two historical randomised trials which compared hypofractionation (52.5–55 Gy in 20
fractions) with control arms of 60–66 Gy in 33 fractions in 6.5 weeks, doses that, by current
standards, are low. The results show a trend towards a lower four-year bNED rate with
hypofractionation.
14,15
The Christie Hospital has reported their experience using 50 Gy in 16 fractions with
a conformal technique. The overall bNED rates at ve years were 82% for low grade;
56% for intermediate and 39% for high risk. These outcomes are comparable to those
achieved using more protracted regimens (Level 2b) with toxicity greater than or equal
to Radiation Therapy Oncology Group (RTOG) grade 2 in 5% for bladder and 9% for
gastrointestinal(GI).
1,16
Nearly 8,000 patients have been randomised into completed and ongoing trials of
hypofractionation; including the Conventional or Hypofractionated High Dose Intensity
Modulated Radiotherapy for Prostate Cancer (CHHiP) trial, the Hypofractionated versus
Conventionally Fractionated Radiotherapy for Patients with Localised Prostate Cancer
(HYPRO) trial, the Scandinavian-led Phase III Study of HYPOfractionated Radiotherapy of
Intermediate Risk Localised Prostate Cancer (HYPO) study, the Canadian PROFIT study
and the North American RTOG 0415 study.
4,17–21
Toxicity of moderate hypofractionation
at two-year follow-up (based on physician reported outcomes) was as low as with
conventional fractionation in the CHHiP study, which compared 74 Gy in 37 fractions to 60
Gy in 20 fractions and 57 Gy in 19 fractions.
4
There is a suggestion that equivalent disease-
free survival (DFS) can be obtained at the expense of increased genitourinary (GU) or GI
toxicity although overall toxicity remains acceptable.
17,22,23
Results, in terms of disease control, from three of the hypofractionation trials have now
been presented in abstract form. The CHHiP trial showed non-inferiority between 60 Gy in
20 fractions and 74 Gy in 37 fractions; the HYPRO study showed non-inferiority between
78 Gy in 39 fractions and 64.6 Gy in 19 fractions; PROFIT showed non-inferiority between
78 Gy in 39 fractions and 60 Gy in 20 fractions and the RTOG 0415 study showed non-
inferiority between 73.8 Gy in 41 fractions and 70 Gy in 28 fractions.
24,25
High-dose-rate (HDR) brachytherapy is an alternative means of delivering hypofractionated
radiation as a boost to achieve dose escalation after 45–46 Gy in 1.8–2 Gy daily fractions
or 37.5 Gy in 15 fractions.
26–28
The ASCENDE-RT trial shows that low dose rate (LDR)
brachytherapy as a boost after 46 Gy in 23 fractions is superior to external-beam 76 Gy in 38
fractions.
28
Profound hypofractionation (dened as 6 Gy per fraction or more) has been shown to be
feasible and safe in cohort studies, with high levels of disease control in low-risk patients.
The Prostate Advances in Comparative Evidence (PACE) trial is randomising between
standard of care (surgery or image-guided intensity-modulated radiotherapy [IG-IMRT]),
and stereotactic radiotherapy (36.25 Gy in ve fractions); HYPO compares 78 Gy in 39
fractions versus 42.7 Gy in seven fractions and has recruited 1,000 patients in Scandinavia
with a target recruitment of 1,920 patients.
18,269
83Radiotherapy dose fractionation Third edition
Postoperative radiotherapy
There is evidence (Grade A) from three randomised trials, that adjuvant postoperative
radiotherapy using 60–64 Gy and 2 Gy per fraction improves recurrence rates in
postoperative patients considered to be at high risk of recurrence.
1,30–29
The optimal timing
of postoperative radiotherapy in this group, whether immediate or at rst evidence of PSA
recurrence, is not known; this and the benet of adjuvant ADT in the postoperative setting
are the two primary questions being addressed in the ongoing Medical Research Council
(MRC) Radiotherapy and Androgen Deprivation in Combination After Local Surgery
(RADICALS) trial, using either 66 Gy in 33 fractions or 52.5 Gy in 20 fractions.
33
Radiotherapy technique
Dose escalation increases the side-eects of treatment. This can be mitigated by
using IMRT or arc techniques (volumetric modulated arc therapy [VMAT] or Rapidarc®)
to minimise dose to the organs at risk. The role of lymph node irradiation remains
uncertain.
34,35
It is possible to identify patients who have a signicant risk of lymph node
involvement, but the results of randomised trials to address the value of elective nodal
irradiation are equivocal. It may be considered for high-risk patients, recognising that the
larger volume is associated with higher toxicity.
IMRT or arc techniques (VMAT or Rapidarc) with appropriate IGRT are the standard of care
when delivering high-dose radiation to the prostate. Fiducial markers or cone beam images
should be used for verication to minimise interfraction variation.
36,37
Recommendations
Radical radiotherapy to the prostate should be delivered using IMRT
or arc (VMAT or Rapidarc) techniques with IGRT verifation. Acceptable
regimensinclude:
74–78 Gy to the prostate in 37–39 fractions over 7.5 weeks (Grade A)
60 Gy in 20 fractions over 4 weeks (Grade A)
Or using a brachytherapy boost:
37.5 GY in 15 fractions over 3 weeks followed by 15 Gy HDR brachytherapy boost
(Grade B)
46 Gy in 23 fractions over 4.5 weeks followed by 115 Gy LDR brachytherapy boost
(Grade B)
Nodal irradiation:
55–60 Gy in 37 fractions over 7.5 weeks or equivalent (Grade D)
Postoperatively:
66 Gy in 33 fractions over 6.5 weeks or
52.5 Gy in 20 fractions over 4 weeks (Grade C)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
1
84Radiotherapy dose fractionation Third edition
Palliative radiotherapy
Palliative radiotherapy may be indicated in the event of troublesome haemorrhage, outow
obstruction or pressure symptoms. There is no evidence to guide fractionation.
Recommendations
For palliation standard schedules are used as follows:
21 Gy in 3 fractions, alternate days over 1 week (Grade D)
20 Gy in 5 fractions over 1 week (Grade D)
30 Gy in 10 fractions over 2 weeks (Grade D)
8–10 Gy single dose (Grade D)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
1
References
85Radiotherapy dose fractionation Third edition
1. www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009
(last accessed 30/9/16)
2. Schmidt-Hansen M, Hoskin P, Kirkbride P, Hasler E, Bromham N. Hormone and radiotherapy versus
hormone or radiotherapy alone for non-metastatic prostate cancer: a systematic review with meta-
analyses. Clin Oncol (R Coll Radiol) 2014; 26(10): e21–e46.
3. National Institutue for Health and Care Excellence. Prostate cancer: diagnosis and management.
Clinical Guideline. Cardi: National Institutue for Health and Care Excellence, 2014.
4. Dearnaley DP, Sydes MR, Graham JD et al. Escalated-dose versus standard-dose conformal
radiotherapy in prostate cancer: rst results from the MRC RT01 randomised controlled trial. Lancet
Oncol 2007; 8(6): 475–487.
5. Creak A, Hall E, Eeles R et al. Randomised pilot study of dose escalation using conformal radiotherapy
in prostate cancer: long-term follow-up. Br J Cancer 2013; 109(3): 651–657.
6. Peeters ST, Heemsbergen WD, Koper PC 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; 24(13): 1990–1996.
7. Pollack A, Zagars GK, Starkschall et al. Prostate cancer radiation dose response: results of the M. D.
Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002; 53(5): 1097–1105.
8. Michalski JM, Moughan J, Purdy J et al. A randomized trial of 79.2 Gy versus 70.2 Gy radiation therapy
(RT) for localized prostate cancer. J Clin Oncolo 2015; 33(suppl 7; abstr 4).
9. Dasu A, Toma-Dasu I. Prostate alpha/beta revisited – an analysis of clinical results from 14 168
patients. Acta Oncol 2012; 51(8): 963–974.
10. Proust-Lima C, Taylor JM, Sécher et al. Conrmation of a low alpha/beta ratio for prostate cancer
treated by external beam radiation therapy alone using a post-treatment repeated-measures model for
PSA dynamics. Int J Radiat Oncol Biol Phys 2011; 79(1): 195–201.
11. Viani GA, Stefano EJ, Afonso SL. Higher-than-conventional radiation doses in localized prostate
cancer treatment: a meta-analysis of randomized, controlled trials. Int J Radiat Oncol Biol Phys 2009;
74(5): 1405–1418.
12. Cahlon O, Zelefsky MJ, Shippy A et al. Ultra-high dose (86.4 Gy) IMRT for localized prostate cancer:
toxicity and biochemical outcomes. Int J Radiat Oncol Biol Phys 2008; 71(2): 330–337.
13. Zelefsky MJ, Pei X, Chou JF et al. Dose escalation for prostate cancer radiotherapy: predictors of long-
term biochemical tumor control and distant metastases-free survival outcomes. Eur Urol 2011; 60(6):
1133–1139.
14. Lukka H, Hayter C, Julian JA et al. A randomized trial comparing two fractionation schedules for
patients with localized prostate cancer. J Clin Oncol 2005; 23(25): 6132–6138.
15. Yeoh EE, Fraser RJ, McGowan RE et al. Evidence for ecacy without increased toxicity of
hypofractionated radiotherapy for prostate carcinoma: early results of a Phase III randomized trial. Int J
Radiat Oncol Biol Phys 2003; 55(4): 943–955.
16. Livsey JE, Cowan RA, Wylie JP et al. Hypofractionated conformal radiotherapy in carcinoma of the
prostate: ve-year outcome analysis. Int J Radiat Oncol Biol Phys 2003; 57(5): 1254–1259.
17. Aluwini S, Pos G, Schimmel E et al. Hypofractionated versus conventionally fractionated radiotherapy
for patients with prostate cancer (HYPRO): acute toxicity results from a randomised non-inferiority
phase 3 trial. Lancet Oncol 2015; 16(3): 274–283.
18. www.controlled-trials.com/ISRCTN45905321 (last accessed 3/10/16)
86Radiotherapy dose fractionation Third edition
19. Radiation Therapy Oncology Group. RTOG 0415. A phase III randomized study of hypofractionated
3D-CRT/IMRT versus conventionally fractionated 3D-CRT/IMRT in patients with favorable-risk
prostate cancer. Philadelphia: Radiation Therapy Oncology Group, 2007.
20. Arcangeli S, Strigari L, Gomellini S et al. Updated results and patterns of failure in a randomized
hypofractionation trial for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2012; 84(5): 1172–
1178.
21. Pollack A, Walker G, Horwitz EM et al. Randomized trial of hypofractionated external-beam
radiotherapy for prostate cancer. J Clin Oncol 2013; 31(31): 3860–3868.
22. Catton CN, Lukka H, Gu C-S et al. Randomized trial of a hypofractionated radiation regimen for the
treatement of localized prostate cancer. J Clin Oncol 2017; 35: 1884–1890.
23. Dearnaley D, Syndikus I, Mossop H et al. Conventional versus hypofractionated high-dose intensity-
modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority,
phase 3 CHHiP trial. Lancet Oncol 2016; 17: 1047–1060.
24. Incrocci L, Wortel RC, Alemayehu WG et al. Hypofractionated versus conventionally fractionated
radiotherapy for patients with localised prostate cancer (HYPRO: nal ecacy results from a
randomised, multicentre, open label, phase 3 trial. Lancet Oncol 2016; 17(8): 1061–1069.
25. Lee W R, Dignam JJ, Amin M et al. Randomized phase III noninferiority study comparing two
radiotherapy fractionation scheduled in patients with low-risk prostate cancer. J Clin Oncol 2016;
34(20): 2325–2332.
26. Hoskin PJ, Rojas AM, Bownes PJ, Lowe GJ, Ostler PJ, Bryant L. Randomised trial of external beam
radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate
cancer. Radiother Oncol 2012; 103(2): 217–222.
27. Helou J, D’Alimonte L, Loblaw A et al. High dose-rate brachytherapy boost for intermediate risk
prostate cancer: long-term outcomes of two dierent treatment schedules and early biochemical
predictors of success. Radiother Oncol 2015; 115(1): 84–89.
28. Morris WJ, Tyldesley S, Rodda S et al. Androgen suppression combined with elective nodal and dose
escalated radiation therapy (the ASCENDE-RT Trial): an analysis of survival endpoints for a randomized
trial comparing low-dose-rate brachytherapy boost to a dose-escalated external beam boost for high-
and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys 2017; 98(2): 275–285.
29. www.isrctn.com/ISRCTN45905321 (last accessed 3/10/16)
30. Wiegel T, Bottke D, Steiner U et al. Phase III postoperative adjuvant radiotherapy after radical
prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative
undetectable prostate-specic antigen: ARO 96-02/AUO AP 09/95. J Clin Oncol 2009; 27(18): 2924–
2930.
31. Thompson IM, Tangen CM, Paradelo J et al. Adjuvant radiotherapy for pathological T3N0M0 prostate
cancer signicantly reduces risk of metastases and improves survival: long-term follow-up of a
randomized clinical trial. J Urol 2009; 181(3): 956–962.
32. Bolla M, van Poppel H, Tombal B et al. Postoperative radiotherapy after radical prostatectomy for high-
risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet
2012; 380(9858): 2018–2027.
33. Parker C, Sydes MR, Catton C et al. Radiotherapy and androgen deprivation in combination after local
surgery (RADICALS): a new Medical Research Council/National Cancer Institute of Canada phase III
trial of adjuvant treatment after radical prostatectomy. BJU Int 2007; 99(6): 1376–1379.
34. Pommier P, Chabaud S, Lagrance JL et al. Is there a role for pelvic irradiation in localized prostate
adenocarcinoma? Preliminary results of GETUG-01. J Clin Oncol 2007; 25(34): 5366–5373.
87Radiotherapy dose fractionation Third edition
35. Lawton CA, DeSilvio M, Roach M 3rd 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; 69(3): 646–655.
36. Zelefsky MJ, Kollmeier M, Cox B et al. Improved clinical outcomes with high-dose image guided
radiotherapy compared with non-IGRT for the treatment of clinically localized prostate cancer. Int J
Radiat Oncol Biol Phys 2012; 84(1): 125–129.
37. Singh J, Greer PB, White MA et al. Treatment-related morbidity in prostate cancer: a comparison of
3-dimensional conformal radiation therapy with and without image guidance using implanted ducial
markers. Int J Radiat Oncol Biol Phys 2013; 85(4): 1018–1023.
