Why less is more – our journey to 5# radiotherapy for prostate cancer

Hypofractionated radiotherapy was a topic of interest long before COVID-19, but the last 12 months has seen an acceleration of uptake in the oncology community. Prostate cancer has been a particular focus as urologists have sought treatment protocols that keep hospital visits to a minimum, without compromising outcomes for their patients.

Our Urology teams at GenesisCare have been frontrunners in the use of hypofractionated techniques and this month we announced that 5# (five fraction) stereotactic ablative radiotherapy (SABR) would now be offered across our network of 14 specialist cancer centres to men with low- to intermediate-risk localised prostate cancer.

Dr Philip Camilleri, a member of the clinical team that has overseen this innovation, explains the clinical evidence that has informed this decision and why hypofractionation is the way ahead.

One of the challenges of low- to intermediate-risk prostate cancer is determining the most appropriate treatment. Clinically, surgery, external beam radiotherapy (EBRT) and active monitoring can offer a similar outcome and numerous studies lend equal support to these treatment approaches[1]. On that basis, decisions are often focused on side effects (particularly gastro-intestinal, genitourinary, and sexual concerns), together with patient tolerability, for example weighing up anaesthetic and intraoperative risks against weeks of radiotherapy.

Typically, a radiotherapy treatment plan for low- to intermediate-risk localised prostate cancer involves 2 Gy daily fractions to a total dose of 74 to 79.2 Gy – total 37-40# over 7 to 8 weeks, or 60 Gy in 20# – 3Gy per fraction –delivered over four weeks. The latter, known as moderate hypofractionation, has been the standard of care at GenesisCare in recent years, after three major non-inferiority phase 3 randomised controlled trials evidenced its safety and efficacy. Our technique has focused on the importance of sculpting dose distribution to avoid early and late gastrointestinal (GI) and genitourinary (GU) toxicity. This is achieved using advanced volumetric arc radiotherapy (VMAT) -which delivers this highly conformal dose distribution – along with innovative techniques such as surface guided radiotherapy and the use of rectal spacers.

There is good evidence to support ultra-hypofractionation resulting from the HYPO-RT-PC trial[3] showing equivalence compared to conventional fractionation for low, intermediate and high prostate cancer patients.  In addition data from large meta-analyses supports the efficacy of ultra-hypofractionation in prostate cancer[4]. As an innovator, GenesisCare have been keen to adopt international best practice. There are obvious benefits, not only in terms of patient preference for this speedier therapy, but there is also a potential therapeutic benefit derived from the radiobiology of prostate cancer that suggests a smaller number of high-dose fractions could improve the therapeutic ratio (indicated by a low α/βratio). So far however, the available evidence would suggest equivalence.

For more information about the α/β ratio, see below.

Ultra-hypofractionated treatments are also known as stereotactic ablative radiotherapy (SABR) as the technique utilises highly precisely targeted high doses of radiotherapy. This is necessary because increasing the dose to the prostate in this way, raises challenges of radiotoxicity to surrounding tissue. At GenesisCare, we are established as a SABR centre-of-excellence, with wide experience treating oligo-metastases and regularly review evidence for other indications that can benefit from this treatment protocol.

The PACE-B trial has shown that treatment for low- to intermediate-risk prostate cancer can be achieved with SABR on a standard linac with no increase in side effects compared with moderately hypofractionated radiotherapy[2]. Based on our extensive experience and governance structures, we are now confident to implement this evidence-based approach across our network and offer low- to intermediate-risk localised prostate cancer patients the option of a 5# regime.

See our to clinical summary of the evidence base below for more information.

To further reduce the effects of toxicity to healthy tissues, in particular the bowel, we are using a rectal spacer insertion technique for every patient undergoing 5# SABR on our conventional linacs. This spacer is inserted under local anaesthetic between the rectum and the prostate to temporarily move the anterior rectal wall further away from the prostate. The aim is to reduce the amount of radiation delivered to the rectum and limit toxicity, thereby reducing bowel, urinary and sexual function related side effects.

5# SABR is an innovation that delivers on many levels. Patient preference is for shorter treatment times and we can do that in a way that provides an equivalent outcome to standard 20 and 39 fraction protocols, but with less overall time. Depending on location, they can choose local treatment on a standard linac and get on with their lives quickly, and with the minimum disruption or longer term impact.

From a clinician point of view, we can treat patients safely, speedily and effectively, offering a viable alternative to surgery which has the opportunity of reducing outpatient visits. As the UK’s leading private cancer provider, GenesisCare has an important role to play, exploring the global evidence-base and introducing new and better ways to treat cancer. In the coming months as we emerge from the pandemic, 5# fraction SABR for prostate, together with other ultra-hypofractionated techniques, will enable more patients to be treated quickly, reducing their dependency on secondary healthcare.

Dr Philip Camilleri is Clinical Director of Urological Cancers, GenesisCare UK, Oxford and a member of the SABR clinical reference group.

If you would like more information about how to access this treatment for your patients, please don’t hesitate to contact urologysat@genesiscare.co.uk 

The linear-quadratic model uses a ratio – the alpha/beta ratio (α/β) – to represent the cell survival of different tissues in response to fraction size. The ratio is inversely related to changes in fraction size, therefore a low ratio indicates a greater sensitivity to increasing fraction size. For most tumours and acute healthy tissue responses, the ratio is over 8 Gy. However, for prostate cancer the ratio may be as low as 1.5 Gy.

PACE-B: acute toxicity findings from an international, randomised, open-label phase 3, non-inferiority trial [2]

PACE-B is a randomised trial of standard-of-care conventionally fractionated or moderately hypofractionated radiotherapy versus five-fraction stereotactic body radiotherapy for low-risk to intermediate-risk localised prostate cancer.

Participants were randomly allocated (1:1) to conventionally fractionated or moderately hypofractionated radiotherapy (78 Gy in 39# over 7-8 weeks or 62 Gy in 20# over 4 weeks, respectively) or stereotactic body radiotherapy (36·25 Gy in 5# over 1–2 weeks). Side effect data collected over the first three months after treatment, show that patients who had SABR had similar and low levels of side effects when compared to the patients who had conventionally fractionated or moderately hypofractionated radiotherapy.

The worst acute RTOG gastrointestinal toxic effect proportions were grade 2 or more severe toxic events (such as, diarrhoea, discomfort in the back passage, or changes in bowel habit) in:

• 53 (12%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group
• 43 (10%) of 415 patients in the stereotactic body radiotherapy group

(Difference −1·9 percentage points, 95% CI −6·2 to 2·4; p=0·38)

The worst acute RTOG genitourinary toxicity proportions were grade 2 or worse toxicity (such as, needing to pass water more frequently, problems passing water or bladder incontinence) in:

• 118 (27%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group
• 96 (23%) of 415 patients in the stereotactic body radiotherapy group

(Difference −4·2 percentage points, 95% CI −10·0 to 1·7; p=0·16).

These results suggest that substantially shortening treatment courses with SABR does not increase gastrointestinal or genitourinary acute toxicity. Late toxicity and efficacy data for the PACE-B trial are awaited.

References

1. Hamdy F, Donovan J, Lane J, Mason M, Metcalfe C, Holding P, et al. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. New England Journal of Medicine. 2016;375(15):1415-1424.
2. Brand D, Tree A, Ostler P, van der Voet H, Loblaw A, Chu W, et al. Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial. The Lancet Oncology. 2019;20(11):1531-1543.
3. Widmark A, Gunnlaugsson A, Beckman L, Thellenberg-Karlsson C, Hoyer M, Lagerlund M, et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial.  The Lancet. 2019 Aug 3;394(10196):385-395.
4. Jackson W, Silva J, Hartman HE, Dess RT, Kishan A, Beeler W, et al. Stereotactic Body Radiation Therapy for Localized Prostate Cancer: A Systematic Review and Meta-Analysis of Over 6,000 Patients Treated On Prospective Studies. Int J Radiation Oncol Biol Phys. 2019;104(4)778-789