Question of Dose, Fractionation and Technique: Ingredients for Testing Hypofractionation in Prostate Cancer – the CHHiP Trial

Clinical Oncology (2008) 20: 12e14 doi:10.1016/j.clon.2007.10.008

Editorial

Question of Dose, Fractionation and Technique: Ingredients for Testing Hypofractionation in Prostate Cancer e the CHHiP Trial V. S. Khoo*, D. P. Dearnaleyy *Royal Marsden NHS Foundation Trust, Chelsea, London SW3 6JJ, UK; yInstitute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, Surrey SM2 5PT, UK

Radiotherapy for prostate cancer is in a most exciting and challenging era. It has benefited from advances in imaging and technology where magnetic resonance imaging has replaced computed tomography as the gold standard staging modality and is complementary in the treatment planning of prostate cancer [1]. Data from a randomised trial support the use of conformal radiotherapy (CFRT) techniques over conventional or unshaped radiotherapy methods in reducing late rectal toxicity, which remains the dose-limiting organ at risk in prostate external beam radiotherapy [2]. Dose escalation within several randomised trials has been shown to improve the control of prostate cancer compared with conventional doses using prostate-specific antigen (PSA) as a surrogate end point [3e7]. These trials have shown an improvement in 5-year biochemical (b) PSA control rates of between 6 and 19% when radiation doses were raised from around 64e70 Gy to 74e78 Gy. The multicentre French Groupe d’Etude des Tumeurs Uro-Genitales (GETUG) CFRT trial that compared randomisation between 70 Gy vs 80 Gy has only reported acute toxicity rates and 5-year outcomes are awaited [8]. However, dose escalation in prostate cancer using CFRT techniques has also caused a significant increase in clinically relevant late rectal toxicity [3e7]. Intensity-modulated radiotherapy (IMRT) can offer the potential to reduce rectal toxicity [9]. This has been shown in a prospective, but not randomised, series of over 770 patients treated at the Memorial Sloan Kettering Cancer Center. In this very large patient cohort, late rectal toxicities were substantially reduced even when the dose was escalated to 81 and 86.4 Gy, with the 3-year actuarial R grade 2 gastrointestinal toxicity being 4% [10]. More recently, the awareness that prostate cancer may have a high fractionation sensitivity due to a low a/b ratio around 1.2e1.5 has been alluded to by several investigators [11e13]. However, there remains considerable uncertainty around this estimate. The latest theoretical review has utilised a comprehensive analysis of 3551 men with prostate cancer treated largely by external beam radiotherapy alone at three centres over a period between 1987 and 2004 [14]. In this analysis, the radiotherapy prescriptions ranged 0936-6555/08/200012þ03 $35.00/0

between 57.4 and 77.4 Gy using daily fraction sizes between 1.8 and 2.86 Gy. Using a proportional hazards model method that stratified for prostate cancer risk and treating institution, the a/b ratios estimated for external beam data were modelled to be higher at 3.7 Gy (95% confidence interval 1.1 to N Gy). Nevertheless, it has been suggested that the rectum, which is the dose-limiting organ in prostate radiotherapy, has an a/b ratio of between 3.6 and 6.0, which is higher than that for either estimate of the a/b ratio in prostate cancer [13]. This suggests that a therapeutic ratio may exist in favour of large dose fractions in prostate radiotherapy with the obvious potential for shorter overall treatment durations. Hypofractionation in prostate radiotherapy might both improve local tumour control and reduce early and late toxicity, provided appropriate dose constraints for relevant normal tissues are respected [15]. There may also be economic advantages and patient convenience in hypofractionated prostate radiotherapy regimens, especially as conventional fractionation schemes using 1.8e2.0 Gy daily fractions are currently taking patients up to 7e10 weeks of treatment. Hypofractionation regimens are familiar in clinical oncology practice throughout the UK and within Commonwealth countries such as Canada and Australia. The Christie Hospital reported on the use of 3.13 Gy per fraction to a total dose of 50 Gy in over 700 T1-4N0M0 patients [16]. This retrospective study reported that late Radiation Therapy Oncology Group rectal toxicity of 5% experienced by these patients was similar to conventional dose regimens using 2 Gy per day fractions to total doses of around 64e70 Gy. It is worth noting that compared with the good prognostic group (T1-2, PSA % 10 ng/ml, Gleason % 6) in this report, the intermediate to poor prognostic subgroups (with one or more than two of these factors being raised) did not fare as well at the total dose of 50 Gy. For these groups, their corresponding bPSA control rates were less than that of published literature. This suggests that these intermediate to poor prognostic subgroups may benefit from dose escalation. There have been two randomised trials comparing hypofractionated and conventional dose schedules. The

ª 2007 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

QUESTION OF DOSE, FRACTIONATION AND TECHNIQUE

smaller trial from Australia included 217 men with T1-2N0M0 prostate cancer and compared 64 Gy in 2 Gy daily fractions vs 55 Gy in 2.75 Gy daily fractions [17]. Equivalent late toxicities and local control rates were reported with a median follow-up of 48 months. The larger trial from Canada with 936 T1-2N0M0 patients compared 66 Gy in 2 Gy daily fractions vs 52.5 Gy in 2.63 Gy daily fractions [18]. With a median follow-up of 68 months, late toxicity was similar between the randomised arms at 3.2%, but the hypofractionated arm experienced a lower bPSA control rate (49% vs 56%), suggesting that the biological dose of the hypofractionated arm was inferior to the conventional dose arm. However, all of these trials are compatible, with an a/b ratio of % 1.5e3 Gy [19]. There are several prospective but non-randomised studies from Canada and the UK with preliminary reports in abstract form suggesting that external beam hypofractionation using 3 Gy per fraction can be safely delivered up to a total of 60e66 Gy over 4e4.5 weeks. It is clear that this potential radiotherapeutic strategy needs to be tested appropriately within formal clinical trials to determine its true potential benefits. Multicentre application of IMRT methods, together with the first randomised comparison of high-dose hypofractionated and standard 2 Gy daily fractions are the ingredients for the CHHiP (Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer) trial. The paper by South et al. [20] examines the application of IMRT by a forward planned IMRT method. The technique improves dosimetry compared with the CFRT planning method used in the international multicentre Medical Research Council (MRC) RT-01 trial. This simple forward planned IMRT technique forms the treatment planning basis for the CHHiP trial and was designed to be readily used by participating centres that do not have the full capability or resources for inverse planning and/or more sophisticated IMRT delivery, such as dynamic IMRT methods. The application of any form of IMRT does require the use of explicit dose constraints. This is mandatory within the CHHiP trial compared with the previous MRC RT-01 trial and clearly outlines the importance of respecting the dose thresholds for all pelvic organs at risk in order to ensure that the benefits of high-dose hypofractionation are realised. The CHHiP trial compares three different dose fractionation regimes: 74 Gy in 2 Gy fractions over 7.5 weeks; 57 Gy in 3 Gy dose fractions over 4 weeks and 60 Gy in 3 Gy dose fractions over 4 weeks. The 74 Gy control arm was based on the escalated arm of the RT-01 trial [4]. The recently reported results from the MRC RT-01 trial showed an 11% improvement in bPSA control rates at 5 years (64 Gy group 60% vs 74 Gy group 71%; hazard ratio 0.67, P ¼ 0.0007). The two selected experimental hypofractionated arms of 57 and 60 Gy were designed to give equivalence in anticipated prostate cancer control for two a/b ratios of 1.5 and 2.5, respectively. In this controlled clinical trial setting, if the a/b ratio was 1.5 then the 57 Gy regimen would be biologically equivalent to 74 Gy, whereas the 60 Gy arm would probably provide better results, as it would be a biologically higher dose. However, if the a/b ratio was

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2.5, then the 60 and 74 Gy arms would be biologically equivalent, whereas the 57 Gy arm would be expected to be inferior. Provided that the a/b ratio for normal tissue side-effects is O2.5 Gy, the experimental treatment arms are predicted to produce less late toxicity. The rationale for the three arms in the CHHiP trial is to generate two points on the experimental hypofractionated dose complication response curves, which should allow extrapolation to an iso-effective dose for tumour control compared with the conventional 2 Gy fractionation schedule. It will also evaluate the true a/b ratio for prostate cancer based wholly on external beam data rather than an estimate from a combination of both external beam and low-dose brachytherapy data. The CHHiP trial has completed its planned first cohort of 150 patients and the second cohort of 300 patients in the third quarters of 2004 and 2006, respectively, for a total of 450 patients. The first part of the CHHiP trial was to evaluate and exclude unacceptable toxicity. It recruited patients from the Royal Marsden Hospital and Clatterbridge Oncology Centre. A recent preliminary report has outlined that both acute and late toxicity rates are comparable between the treatment arms and within the range expected from published studies [21]. The second part of the CHHiP trial was supported by a Department of Health grant and expanded patient recruitment to 12 UK centres. This part of the trial was to refine estimates of acute and late toxicity rates between the treatment arms. These safety data were essential for gaining further approval (Clinical Trials Advisory and Awards Committee (CTACC) with Cancer Research UK funding) for nationwide recruitment into the CHHiP trial for its third and final cohort. This third part of the trial plans to recruit 1713 prostate cancer patients for a total of 2163 from all three parts of the trial. It is designed as a non-inferiority study where 721 patients for each of the treatment arms will enable 90% power with one-sided alphas of 0.05 of detecting differences of 7%. With respect to the level of treatment-related toxicity, 659 patients per hypofractionated arm will provide 90% power to exclude R 16% complication rates if the conventional dose arm of 74 Gy has a R 2 Radiation Therapy Oncology Group toxicity level of 10%. Up to 12 centres are participating in the CHHiP trial to date and clinical participant updates are held 2 monthly via teleconference. At the last CHHiP teleconference meeting in July 2007, 271 patients have already been randomised into the third phase of the CHHiP trial for a total of 722 patients overall. A further 25 centres have expressed interest in CHHiP and are progressing through the pre-trial quality assurance programme. If all centres expressing interest in CHHiP do participate, then the total number of centres at 37 will exceed the number of centres that participated in the MRC RT-01 dose escalation trial. Currently, the accrual in CHHiP is approximately 24 patients a month, but if the new centres are able to recruit enthusiastically, we hope to increase patient numbers to 30e40 per month, which will readily meet the trial timelines. Further centres, both in the UK and internationally, are welcomed to participate in the CHHiP trial. Interested parties are invited to contact the co-ordinating

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CLINICAL ONCOLOGY

group at the Institute of Cancer Research Clinical Trials and Statistics Unit (CHHiP trial co-ordinator e-mail: [email protected]) for further information. It is clear that both radiobiological developments and technical radiotherapy advances have provided the opportunity to appropriately exploit and explore the clinical value of dose escalation using hypofractionation and IMRT for prostate cancer. These questions of dose, fractionation and technique, which are ingredients of the CHHiP trial, are being formally addressed within a prospective randomised clinical trial such that the true benefits in patient outcomes can be adequately validated. Acknowledgement. This work was undertaken in the Royal Marsden NHS Foundation Trust who received a proportion of its funding from the National Health Service Executive; the views expressed in this publication are those of the authors and not necessarily those of the National Health Service Executive. This work was supported by the Institute of Cancer Research, the Bob Champion Cancer Trust and Cancer Research UK Section of Radiotherapy grant number C46/A2131. The second part of the CHHiP trial received funding from the Department of Health with the third and final part of the CHHiP trial receiving funding from Cancer Research UK. Author for correspondence: V. Khoo, Royal Marsden NHS Foundation Trust, Fulham Road, Chelsea, London SW3 6JJ, UK. Tel: þ44-20-7808-2788; Fax: þ44-20-7811-8017; E-mail: vincent. [email protected] Received 31 July 2007; received in revised form 30 September 2007; accepted 16 October 2007

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7 Dearnaley DP, Sydes MR, Graham JD, et al. Escalated-dose versus standard-dose conformal radiotherapy in prostate cancer: first results from the MRC RT01 randomised controlled trial. Lancet Oncol 2007;8(6):475e487. 8 Beckendorf V, Guerif S, Le Prise E, 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;60(4): 1056e1065. 9 Khoo VS. Radiotherapeutic techniques for prostate cancer, dose escalation and brachytherapy. Clin Oncol (R Coll Radiol) 2005; 17(7):560e571. 10 Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys 2002;53(5):1111e1116. 11 Fowler J, Chappell R, Ritter M. Is alpha/beta for prostate tumors really low? Int J Radiat Oncol Biol Phys 2001;50(4): 1021e1031. 12 Brenner DJ, Martinez AA, Edmundson GK, Mitchell C, Thames HD, Armour EP. Direct evidence that prostate tumors show high sensitivity to fractionation (low alpha/beta ratio), similar to late-responding normal tissue. Int J Radiat Oncol Biol Phys 2002;52(1):6e13. 13 Dasu A. Is the alpha/beta value for prostate tumours low enough to be safely used in clinical trials? Clin Oncol (R Coll Radiol) 2007;19(5):289e301. 14 Williams SG, Taylor JM, Liu N, et al. Use of individual fraction size data from 3756 patients to directly determine the alpha/beta ratio of prostate cancer. Int J Radiat Oncol Biol Phys 2007;68(1):24e33. 15 Hoskin PJ, Dearnaley DP. Hypofractionation in clinical trials for prostate cancer. Clin Oncol (R Coll Radiol) 2007;19(5): 287e288. 16 Livsey JE, Cowan RA, Wylie JP, et al. Hypofractionated conformal radiotherapy in carcinoma of the prostate: five-year outcome analysis. Int J Radiat Oncol Biol Phys 2003;57(5): 1254e1259. 17 Yeoh EE, Holloway RH, Fraser RJ, et al. Hypofractionated versus conventionally fractionated radiation therapy for prostate carcinoma: updated results of a phase III randomized trial. Int J Radiat Oncol Biol Phys 2006;66(4):1072e1083. 18 Lukka H, Hayter C, Julian JA, et al. Randomized trial comparing two fractionation schedules for patients with localized prostate cancer. J Clin Oncol 2005;23(25):6132e6138. 19 Bentzen SM, Ritter MA. The alpha/beta ratio for prostate cancer: what is it, really? Radiother Oncol 2005;76(1):1e3. 20 South C, Khoo VS, Naismith O, Norman A, Dearnaley DP. A comparison of treatment planning techniques used in two randomised UK external beam radiotherapy trials for localised prostate cancer. Clin Oncol (R Coll Radiol) 2007;20(1):15e21. 21 Dearnaley D, Norman A, Syndikus I, et al. Conventional or hypofractionated high dose intensity modulated radiotherapy for prostate cancer (CHHIP) e a phase III multicentre trial. Preliminary report on acute and late toxicity (ISRCTN97182923). The 2007 Multidisciplinary Prostate Cancer Symposium, 2007, Orlando, Florida. American Society of Clinical Oncology (ASCO) Program/Proceedings [abstract 303].