The best radiotherapy for the treatment of prostate cancer involves hypofractionation

Arguing against the Proposition is Alan E. Nahum, Ph.D. Dr. Nahum's Ph.D. is on Theoretical Radiation Dosimetry from Edinburgh University in 1975. After four years teaching science in schools he joined the Medical Physics Department at Umeå University in Sweden, where his work was primarily on ion-chamber correction factors and dosimetry codes of practice, including a sabbatical at NRCC, Ottawa with Dave Rogers. From 1985 to 2002 he worked at the Royal Marsden Hospital/Institute of Cancer Research, UK, where his research dealt mainly with "biological modelling," especially tumor control probability (TCP) and normal tissue complication probability (NTCP). Short spells at Fox-Chase Cancer Center, Reggio Emilia, and Copenhagen followed. Dr. Nahum currently works at the Clatterbridge Centre for Oncology in the UK and is Visiting Professor at Liverpool University, where his major interest is in using TCP and NTCP models to optimize radiotherapy treatment plans. Four clinical analyses of the ratio of prostate tumors were published between 1999 and 2003 yielding values of 1.5, 1.45, 1.2 and .3–7 The last differed from the first three in that unrealistically early repopulation start-up times (0–28 days) were assumed, otherwise the value would have been similar to the others. Provided the ratio for prostate tumors is not above that for late rectal damage (about ), hypofractionation should be safe. Using a calculated reduced total dose (and overall times not too short), there should be no change in late complications or tumor control from conventional schedules. Hypofractionation to reduce fraction number is clearly the "best treatment" for patients' convenience and for less costly healthcare. Hypofractionation is safe, especially when delivered with intensity modulated radiotherapy (IMRT). In London, in 12 fractions and in 6 fractions were used for prostate radiotherapy without major complications.8 The Manchester group recently reported that 705 patients treated with 16 fractions of achieved equivalence to 33 fractions of ,9 which is only true if is about . It is clear that 28 fractions of are feasible,10 as are 22 fractions of (Ritter, personal communication), 20 fractions of (Toronto and UK, personal communications), 9 fractions of ,11 5 fractions of ,12 6 fractions of ,13 and 4 fractions of .13 The intriguing aspect is that there may be a biological bonus for patients. If is significantly lower than then, for equal late rectal reactions, the biological effect on the tumor should be greater for hypofractionated than for conventional treatments. Surprisingly large gains are predicted if and for rectum and prostate tumor, respectively.1 For a schedule of 10 fractions of , the rectal normal tissue tolerance dose (in 2-Gy equivalent fractions) is only for a tumor dose equivalent of .1 Evidence is mounting that is indeed about . Lukka et al.14 randomized 936 patients to 20 fractions of vs 33 fractions of in a Canadian trial. The ratio was determined to be (95% confidence interval (CI): , ,).15 This is one of the best datasets and illustrates the problem of identifying values within clinical 95% limits. For example, an Italian nonrandomized trial16 with 334 patients yielded a point value of (95% CI: , ,)15 but, because of the wide confidence interval, this abnormal value can be discounted as evidence that the for prostate cancer is high. From the work of Demanes et al.,17 we know that is less than . They published 5 to 10 year results of 209 patients treated with external beam radiotherapy (20 fractions of ) + high dose rate (HDR) brachytherapy (4 fractions of ). For intermediate-risk prostate they found 96% tumor control at 5 years, yielding (, , 95% CI). Modeling using would predict 75% tumor control (chi-squared difference from , ).18 This demonstrates that is significantly less than , and opens the door to expecting tumor gains with hypofractionation. I claim the debate. Further clinical trials should be done to improve precision of ; but we need fear neither the loss of prostate tumor control from hypofractionation, nor complications, if dose reduction is done appropriately. Current conventional external-beam radiotherapy for prostate tumors involves between 64 and delivered in 2-Gy fractions. The higher doses are made possible by employment of 3D conformal therapy, most recently IMRT, at many radiotherapy clinics. Local control rates are generally excellent except for advanced disease.19 Additionally, impressive control rates have been obtained for early-stage disease using low dose rate brachytherapy with I-125 seeds.20 Thus, in general, radiotherapy for prostate tumors works well when delivered using conformal techniques. Where, then, does the idea of hypofractionation come from? The answer is that it comes from radiobiological modeling in which the (biochemical) control rates from external-beam therapy have been compared to those from low dose rate brachytherapy.4 Several such studies5,7,21 have claimed to demonstrate that the value for prostate cancer is about , which is lower than that for the surrounding normal tissues. This led my jousting partner Professor Fowler to advocate fraction sizes much larger than , coupled with a corresponding decrease in the total dose to ensure isoeffective complication rates.1 Yes, if it really is true that the effective for prostate clonogens is of the order of , then this hypo-strategy should yield higher control rates than the current /fraction treatment schedules. But is the for prostate cancer low? Are there any published modeling analyses which do not yield a low Yes. Firstly, the use of a tumor control probability (TCP) model incorporating both inter-patient variation in radiosensitivity and hypoxia,2,22 together with mean radiosensitivity values taken from the radiobiological literature, suggested that need not be low. In fact, the mean value derived from in-vitro radiobiological clonogenic assays was .2 Secondly, can we deduce anything from documented treatment outcomes involving relatively large fractions? One thinks of the Christie Hospital in Manchester which has routinely employed -Gy fractions. In fact, their recently published prostate outcome data9 are consistent with the predictions of the heterogeneous radiosensitivity-hypoxia TCP model referred to above,2,23 i.e., this also did not suggest that prostate is low. Thirdly, if a low favors hypofractionation then conversely it must impede a hyperfractionated schedule. Recently, however, a group in Milan reported on a twice-a-day vs once-a-day treatment series.16 Were control rates worse for the patients treated with fractions? Not at all. Outcome was markedly better for the than the patients. The statement being debated is that the best radiotherapy for treating prostate cancer should involve hypofractionation. Taking together the current generally high rates of freedom from biochemical failure achieved with modern conformal therapy using fractions at (escalated) total doses,19 the considerable theoretical doubts cast on the radiobiological modeling which yielded , and the apparently good clinical outcomes recently reported from doing exactly the opposite of hypofractionation, i.e., hyperfractionation,16 I conclude that hypofractionated radiotherapy for prostate cancer is contraindicated. The old adage "if it ain't broke don't fix it" seems appropriate. Dr. Nahum, you're not listening! Hypofractionation for prostate cancer came from biological insight24 not a comparison of external-beam radiotherapy and low-dose-rate brachytherapy, and this before there were other 5-y results. Since then, comparisons have all been at high dose-rate, either with HDR brachytherapy (Brenner et al.,6 giving ; Demanes et al.,17 ; Martinez et al.,25 ) or with head-to-head linear accelerator trials (Lukka et al.,14 ; Kupelian et al.,26 ). Good clinical results are worth a hundred models. Modeling tumor TCP with hypoxia is notoriously unreliable, with or without reoxygenation or inhomogeneities! The single clinical exception mentioned by Dr. Nahum, has been dealt with by Bentzen and Ritter,15 who demonstrated that the value of from the Valdagni et al. nonrandomized clinical trial,16 had 95% confidence limits extending down to .14 Bentzen and Ritter suggested that perhaps the two fractions/day control schedule of Valdagni et al. suffered from incomplete repair. That was a penetrating comment because, if were really low (instead of ), it would cause incomplete repair to contribute disproportionately more to the tumor effect, by reason of the high repair capacity of prostate cancer cells. Then the control arm would have an inflated effect, as reported. Concerning in vitro values that showed a high ratio, they are not relevant. Carlson et al.27 found that in vitro values had little relationship to in situ values, and concluded that for prostate tumors is low. If better tumor results can be obtained with the same or fewer complications, for half the number of fractions or less17,25,26 than the conventional 1.8 or schedules, should we deny this unique biological bonus to patients? This question is settled by the good clinical hypofractionated results already quoted. Professor Fowler is absolutely right when he asserts that hypofractionation is the "best" treatment from the point of view of patients' convenience and healthcare economy (at least in the macroeconomic sense; we are not discussing here the issue of individual clinics gaining more income from prolonged, complex treatments such as multifractionated IMRT). But this is about medical science not economics. It is not about patients' convenience. What we are debating is whether hypofractionation is likely to lead to better clinical outcomes (i.e., uncomplicated cure rates) than the presently practised treatments at about /fraction. There are basically two aspects to this issue, the theoretical one and the clinical results one. Theoretical—any impartial observer would conclude that the theoretical case for a low prostate-clonogen and thus for hypofractionation is deeply flawed, relying on a paucity of clinical data, in particular on one single published brachytherapy study—a case of comparing apples (brachy) with oranges (external-beam). Clinical—preliminary results from some new hypofractionation studies are emerging which do not immediately kill stone dead the hypo-idea, but it is simply too early to draw definite conclusions. Conversely there is an extensive and well-documented study of patients treated with moderate hypofractionation (at about /fraction) from Manchester, UK (Ref. 9) which did not demonstrate superior results and which is perfectly consistent with an ratio of around .23 A study of hyperfractionation16 also yielded clinical outcomes inconsistent with a low . But there are other considerations—if we currently fail to control a significant number of prostate tumors due to hypoxia,22 then how much worse is this likely to be when much larger fractions are used with the probable consequent impairment of reoxygenation between fractions? In conclusion, hypofractionated radiotherapy undoubtedly has its place, especially when coupled with excellent conformality, as the extracranial stereotactical treatment of early-stage lung tumors amply demonstrates.28 Given the current generally excellent results using conformal prostate radiotherapy at about /fraction, however, and the severe doubts cast on the theoretical concept of a low , I conclude that to hypofractionate prostate treatments is to take unnecessary risks with the health of patients suffering from prostate cancer.

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