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What Can we Expect from Dose Escalation Using Proton Beams?
Clinical Oncology (2003) 15: S10–S15 doi:10.1053/clon.2002.0182
What Can we Expect from Dose Escalation Using Proton Beams? J. F. Fowler Department of Human Oncology, Medical School of the University of Wisconsin, Madison, Wisconsin, U.S.A. ABSTRACT: It has been demonstrated without doubt in the literature, including elsewhere in this issue, that much better conformal dose distributions in radiation therapy can be obtained with proton beams than with photons (X-rays) or electrons. It is also clear that this remains entirely true – for the fundamental reason of particle range – even after the latest and projected developments in computer-generated IMRT (intensity-modulated radiation therapy) photon dose escalation are fully considered. We consider several examples of tumour dose–response curves that illustrate the quite large gains to be obtained when dose escalation can be achieved, if normal tissue complications can also be avoided. Two contrasting types of tumour are considered in detail, prostate tumours and non-small-cell lung carcinomas. There is a considerable way to go yet to achieve really high non-recurrence rates, especially in the lung tumours. Proton beams would make this progress much safer and more effective than any variants with photons. Fowler J. F. (2003). Clinical Oncology 15, S10–S15 2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved. Key words: Proton range, intensity-modulated radiation therapy, tumour dose–response, normal tissue complications Received: 2 October 2002
Introduction
‘Dose uniformity in the target and minimization of toxicity in healthy tissues are requirements that, with conventional treatment methods, are often incompatible’ [1]. It is demonstrated in many articles in the literature that protons have the potential to significantly improve current dose distributions [1,2] – even the most advanced forms of IMRT (intensity-modulated radiation therapy). In the present paper we illustrate that the gain in tumour control can be very large, together with much less exposure of normal tissues. First we must emphasize why proton beams are so much more effective than photon beams, and then we shall deal with the corresponding dose–response curves. Early in their development, malignant tumours consist of very few cells and they are well localized. As they develop, they tend to spread to other organs or even, through blood or lymph drainage, to distant organs as metastases. When the disease is confined a local treatment such as surgical excision or radiation therapy is preferable, and the results are often successful. If however regional spread has occurred surgery will not be a good option: chemotherapy with or without radiotherapy is likely to provide a better result. This is where the most recent methods of diagnosis, which are currently being rapidly developed, are very important. Author for correspondence: Dr J. F. Fowler, Department Human Oncology K4/316, 600 Highland Ave, Madison WI 53792, U.S.A. Tel: 608-265-0506 or home: 608-231-5896; Fax: 608-263-9947 or home: 608-231-5897; E-mail: jff[email protected] 0936–6555/03/010S10+06 $30.00/0
Accepted: 17 October 2002
The longer a patient has a viable tumour before diagnosis and treatment, the more likely the tumour is to ‘break out’ as a metastasis, which much reduces the lifespan of a patient. The possibility of such a ‘breakout’ makes local control from a local treatment, such as radiotherapy, vital to achieve. Doses that are slightly too low represent complete failures. Tumour control might be achieved in principle by increasing the radiation dose – but this cannot be done precisely and nonspecifically because the physical properties of photon beams deliver too much dose to surrounding normal tissues. Even the narrowest or sharpest-edged beams of X-rays unavoidably do this, because every beam of photons continues to penetrate through the tumour. Photon beams are attenuated only gradually as they go through any substance. Therefore the photon doses to tissues just behind each tumour are similar to those within the tumour, unless the tumour is very large. The opposite is true of proton beams, which stop completely at a finite range that can be set at the far edge of a target volume. One obvious way of elevating a dose within a tumour volume is to keep a beam of X-rays aimed at the tumour and to revolve the X-ray machine around the tumour, or in alternative geometries to revolve the patient slowly in front of an X-ray machine. This will obviously deliver the highest dose to the tumour whilst spreading out the dose to other tissues all round it. Both these methods have been used, together with non-radial directions that can be delivered with three-dimensional (3D) conformal photon or proton radiotherapy but not with ordinary
2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
step-and-shoot tomotherapy. Within the last few years giant strides have been made in computerized ways of delivering such photon beams, using basically cylindrical shapes of beam-aiming points from outside the patients’ bodies. Such methods are called IMRT because the intensity of the beams is also varied to deliver less radiation when passing through more sensitive parts of the anatomy [3]. A particularly sophisticated form of IMRT is helical tomotherapy where the patient is moved on a couch through the axis of a linear accelerator producing X-rays mounted on a circular frame like a computerized axial tomography (CAT)-scanner. A simultaneous image is continuously recorded of the treatment volume actually being irradiated, so that the treatment could subsequently be altered if desired to compensate for any divergencies in dose or volume [4]. This refinement is called adaptive radiotherapy. All of these advances in delivery of photon (or electron) therapy are already showing improved results in decreased complications, and significantly improving longterm local control when doses have been escalated [5,6]. There are clearly significant gains still to come from using these new methods of photon delivery in certain other disease sites, although not as large as the gains from the use of protons. The total integral dose delivered to a length of say a patient’s trunk comprising the whole volume irradiated by any photon method is not significantly different no matter how ingeniously the beamlets of X-rays are directed. It is much the same as the integral dose delivered from a simple two or four-field box technique. There is still an open question about whether the quite low, but perhaps not negligible, radiation doses which are then being spread over larger volumes of the patients’ anatomies could lead to some untoward effects in future. There have been some basic radiobiological suggestions that this might be so [7,8], but until some definite evidence emerges, the radiation oncology community seems inclined to say ‘that’s just crying wolf’ and to risk the X-ray IMRT strategy. The reason why proton beams are always better at providing treatment dose distributions than photons is both fundamental and simple. Protons beams have a definite range, with negligible ‘spallation’ or forward projection of other particles beyond the end of that range. This is the essential, and very large, advantage that they have over the photons, which are attenuated gradually in tissue and therefore deposit significant doses beyond the target volume. Protons are also better than heavier nuclear particles in this respect of forward projection of spallation. Protons also have the advantage of a build-up of ion density and thus biological effect within a few millimetres of the end of their well-defined track, in the well-known Bragg peak, which helps in achieving the sharpness of the end of their range. The reason why the obviously superior physics of proton beams is not yet employed more widely is the size and expense of proton-generating machines. Of course
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dedicated proton generators for cancer treatment would come down in cost as soon as more were manufactured, and they need not be as unwieldy (or inaccessible) as those machines built originally in physics departments. They would be designed with multiple beam portals so that six or eight patients could be treated simultaneously. At present more than 30 proton machines are in use worldwide for cancer treatment or in planning in various countries. These can be read about in the newsletter ‘Particles’, sponsored as a charitable organization by the Particle Therapy Co-Operative Group, produced by their Secretary Dr Janet Sisterson, at the Harvard Cyclotron Laboratory, Massachussetts General Hospital, 30 Fruit Street, Boston, MA 02114, U.S.A. There are also about 20 websites on this topic in various countries. The contrast between doses to normal tissues and higher doses to tumour volumes is much greater with proton beams than with photons. There is no doubt that the protons beams will provide better dose distributions for curative radiotherapy that any present radiotherapy photon techniques. The question seems to be how much better do we need to see it is, before we decide we want it? Although reasonably high levels of local control can be achieved with radiotherapy now in some cancer sites, they fall far short, in all except a few sensitive types or very small tumours, of the 95–100% long-term success rates that can be obtained with combinations of surgery and radiotherapy in early-stage breast cancer or with radiotherapy only in early-stage carcinoma of the cervix.
Materials and Methods
Now that we have explained the basic superiority of protons over photon beams, we can analyse the resulting expected gains in tumour control. There can no longer be any doubt that higher doses in radiotherapy can lead to higher rates of tumour control, (unless local control is already above 90%). However some clinical studies have been too small to show statistical significance, and much is made of these by the nay-sayers. As explained above, the necessary higher photon doses cannot at present be given because of complications in normal tissues, although gradual progress in conformal 3D and IMRT treatments is demonstrating that dose escalation is in principle feasible. As well as two careful and comprehensive studies in the 1990s of many types of tumour [9,10], two recent, very detailed, institutional studies of prostate cancer published in the same recent edition of the Int J Radiat Oncol Biol Phys 2002 [5,6] leave no doubt at all that significant increases in biochemical control of PSA level at 4–5 years after treatment occur with increases in total dose. Further, detailed analyses of one of those studies make it clear that the dose–response curves become steeper when the prognostic factors of subgroups of patients can be characterized in more detail [11]. This means that for any individual patient the gain in tumour effect will be larger than the average
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values obtained from groups of patients, which are the only values that we can determine from clinical results. Dr Herman Suit has also recently summarized these conclusions succinctly in a wide-ranging review of advances in radiotherapy [12]. That paper also made it clear that the most effective way of increasing dose in a tumour target volume whilst minimizing dose in neighbouring normal tissues is to use proton beams. This physical superiority of proton tissue doses is clear [1,2,11,12], in spite of the impressive advances recently made in the delivery of photon beams as referred to above [3,4]. We shall review a selection of dose–response curves in order to gain some insight into the increases of tumour control expected from various dose escalations.
Results and Discussion
The certainty with which an increased of dose in radiotherapy has been associated with increases in local control, and more importantly in progression-free survival, have increased over the last 10 years. In an earlier reference [9], the median specific increase of local control for 17 types of tumour averaged 1.65% per 1% increase of total fractionated dose. In the second early reference [10] 50 values of the slope of tumour dose–response curves were analysed, ranging in slope from 0.3% to 47.3 with a median slope of 1.45% per %. (This is a common way of describing the rate of increase of tumour control with total dose, known as the gamma-50 slope of the dose–response curve [13]. An alternative method is to give the absolute % increase of local control (or survival) per Gray of dose, and discussions about the merits of both methods continue.) Neither method is easily applicable to schedules with different sizes of dose per fraction, which therefore have to be stated. The two values of gamma-50 quoted of 1.4 to 1.65 illustrate that if an increase of 10% in total dose is delivered to a given tumour site, an absolute increase of 14 to 17% can be expected in the corresponding local control (or survival). As will be shown below, this is rather a modest increase of effect, which would require several hundred patients in each of two arms of a clinical trial to demonstrate at the usual level of significance. Reference has been made above to the well known steepening of tumour dose– response curves when sufficient diagnostic or prognostic detail is available to narrow the spread of variables within any one group of patients ([11]; Figs 4 and 5 where the gamma 50 values for three discrete ranges of prostate cancer risk range from 4.6–5.2, being much sharper than the values of 1.4–1.65 mentioned above). By such means – and prognostic factors are being discovered at an increasing rate – the steepness of tumour response curves can be expected to increase in the future. There has however been no doubt from the earliest days that sizeable clinical trials are necessary to determine that a clinical increase in local control reaches this level of significance. From the modest slopes mentioned
above, a 10% increase of dose at the tumour would yield a 14 (or 17)% increase in local control, which requires about 250 (or 175) patients at each of two dose levels, a total of 500 (or 350) patients in all. An increase in dose of 20% (or the equivalent in biological effect) requires about 130 patients in each group, a total of 260 in all. It is easy to see that a modest increase of only 10% in local control, or whatever endpoint is determined, would require two groups of patients of about 500 in each, or 1000 in all. But we may look forward to steeper dose–response curves in future as explained above.
Prostate Tumour Dose Escalation
We shall take two types of tumour as representing two extremes of the spectrum of difficulty in effecting a long-term cure of cancer. The first example is that of prostate cancer, that has now replaced lung cancer as the commonest male cancer. It is for this type of tumour that the recent examples of relative success in long-term cure (no increase in PSA at 4–5 years) have been reported for escalation of total dose from 70 to 78 Gy [5] and from 66 to 81 or 86.4 Gy [6]. We modelled Fig. 1 from the available published data for survival of patients without recurrence of PSA at 4–5 years from five well known prostate treatment centres, with 10 dose levels of external 3D conformal or IMRT beams [14]. The resulting logistic regression curve is shown, having a TCD50 of 66 Gy (in 2 Gy fractions, that is, normalized total doses NTD) and a gamma-50 slope of 2.1. Since not all the centres used doses of 2 Gy (range 1.8–2.2 Gy), the total doses were normalized using the value of alpha/beta=1.5 Gy for prostate tumours which we determined in the same paper [14]. This was a small correction as described in that paper. We have subsequently used this regression curve to predict the increases in bNED when various amounts of dose escalations were modelled. It is well known that slowly proliferating normal tissues in which late complications occur have a high sensitivity to altered dose per fraction, which means that they have small alpha/beta ratios, indicating large capacities for repair between fractions (beta in the Linear Quadratic formula) compared with their intrinsic radiosensitivities (alpha). The same trend applies to malignant cells in tumours [14]. Because prostate malignancies are unique among tumours in proliferating slowly, and therefore in having very low values of the ratio alpha/beta, they enable a special advantage to be obtained from the use of larger doses per fraction, called hypofractionation. The outstanding conclusion was that hypofractionation (with a carefully calculated reduction of total dose assuming alpha/beta=3 Gy to maintain constant late rectal effects) could give very large increases of bNED, with no increase of rectal complications. For example changing from 36 fractions of 2 Gy to 15 fractions of 3.6 Gy gave a predicted increase from 69 to 85% bNED at 5 years. Further hypofractionation to 10 fractions of
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Fig. 1 – Logit regression curve of biochemical no evidence of disease (PSA) at 4–5 years after external beam treatment from the five treatment centres referenced in Ref. [14]. The abbreviations in this figure’s key are in sequence Alabama, Fox Chase Cancer Center, William Beaumont Hospital, Memorial Sloan Kettering Institute, and the MD Anderson Cancer Center. This dose–response curve is discussed further in Ref. [14] together with the definition used of intermediate risk. Reproduced with permission of the publishers of Int J Radiat Oncol Biol Phys from Ref [14].
4.7 Gy would increase the predicted bNED to 90%, all with no increase in rectal complications [15]. While this should be quite possible with existing X-ray technology, (because the dose to cure 50% of prostate tumours is only about 66 Gy in 2 Gy fractions), it would be easier and require simpler treatment planning with proton beams. Levegru¨n et al. [11] in analysing their own data from the Sloan Kettering Institute obtained much steeper curves with gamma 50 values of 4.6 to 5.2, presumably from the smaller variations in a single institute study. These data suggest that it might be even easier to achieve such gains, approaching 100% bNED with suitable dose escalation, even for intermediate risk prostate tumours. The use of proton beams will eventually be required to achieve those maximal results.
Non-Small-Cell Lung Cancer (NSCLC) Dose Escalation
The second example is non-small-cell lung cancer (NSCLC), which is increasingly being diagnosed by spiral CT imaging as early-stage small tumours. The results of a carefully conducted clinical trial of photon dose escalation by the University of Michigan at Ann Arbor were published by Martel et al. [16]. Doses were given at 2 Gy per day five times a week so that 90 Gy required 9 weeks of radiotherapy. The characteristics of the curve for the survival of patients without tumour progression at 30 months were given as TCD50=84.5 Gy with a gamma-50 slope of 1.5 [16]. This curve is traced in Fig. 2, and the striking difference from the curve for prostate tumours is clear. The dose to
‘cure’ 50% of lung tumours was 84 Gy, which is 18 Gy or nearly 30% higher than for the prostate tumours, and that makes an enormous difference. This might be a reflection of the fact that most lung tumours are much larger, even at diagnosis, than the prostate tumours, which are currently detected by the serum marker PSA. Second the dose–response curve for NSCLC is flatter than that for prostate tumours. This is likely to be a reflection of a larger range in size at treatment of the lung tumours. The practical conclusion is that even at a dose of 70 Gy (in one or two X-ray fractions per day), no more than about 20–25% disease-free survival at 30 months is expected for patients with NSCLC. This is indeed about the best that any photon radiotherapy can do at present. Doses less than 70 Gy give correspondingly more depressing results, and failure to eliminate the primary tumour is an open invitation to metastasis. Examples of slightly better results from slightly higher doses (plus chemotherapy) are given recently by Rosenman et al. [17]. The case for higher doses is very clear, as the Ann Arbor results have demonstrated, but normal tissue damage, especially pneumonitis, prevents it, except in the special case of selected small volumes as in the pioneering study at Ann Arbor, where they have been able to go up to 103 Gy for the smallest volumes irradiated. They reported one recurrence at 90 Gy out of three patients, which is not surprising because the curve in Fig. 2 does not predict more than about 60% local control at that dose. This is a situation where dose escalation, using the photon-specific IMRT method of spreading dose out widely around the tumour, that is, shared between much
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there is no alpha/beta (slow proliferation) advantage for the fast-growing lung tumours as there is in the slowgrowing prostate tumours. The ‘stereotactic ablation’ of lung tumours is being experimented with, but it will be very much easier and safer to use proton beams, with their much lower spreading of dose among many other tissues, at about half the spread with photons.
Conclusions
Fig. 2 – Logit regression curve for survival without disease progression at 30 months in non-small-cell lung cancer, reconstructed from the parameters quoted by Martel et al. in Ref. [16]. Their actual clinical data had been accumulated up to about the TCD50 dose level at that time. Reproduced with permission from the publishers of Int J Radiat Oncol Biol Phys, in part from Mehta M, Scrimger R, Mackie R. et al. ‘A new approach to dose escalation in non-small-cell lung cancer’. Int J Radiat Oncol Biol Phys 2001;49:23–33.
larger volumes of lung which each receive smaller doses per unit volume, cannot work well. That is because the limiting dose to lung is correlated with the mean lung dose. The smaller doses that spread away from the target volume in 3D conformal therapy are here deleterious. As explained in the introduction, the integral photon dose to a whole trunk is fairly independent of how it is spread out within the trunk, so concentrating the dose in the target at the expense of much larger volumes given lower doses is not likely to work in this disease site. It was only possible in the Ann Arbor dose escalation studies in those tumours which were very small and which required very small target volumes. An extension of such studies originated in Stockholm from brain stereotactic irradiations [18]. It is being pursued in Japan and in Indianapolis, U.S.A. where small tumours and small volumes of lung can be selected for stereotactic irradiation, with a volume limitation that we are still learning about, possibly related to the unusually rapid rate of fall-off with dose outside the small stereotactic fields. A further problem with conventional dose escalation is that 100 Gy (to an appropriately small volume) would take 10 weeks to administer, and yet NSCLC tumours proliferate rather fast, almost as fast as head and neck tumours [19]. Hypofractionation might reduce overall times by a few weeks, but the large doses per fraction mentioned in the context of prostate tumours above are not permissible, because
There are now several examples of dose escalation which demonstrate that local control and survival can be significantly increased if higher doses are used [5,6,11,12,17]. There are other examples where the use of radiotherapy with or without surgery has reduced recurrences to less than 10%, especially in cancer that can be detected early by new techniques. A study of dose–response curves in other sites shows that there is a considerable way to go in achieving sufficiently high doses to reach these levels of success. Improvements are taking place, but they taking place very slowly. One of the surest ways of improving tumour control is by delivering adequate radiation dose, as illustrated above; but normal tissue damage must not be increased. The avoidance of normal tissue dose is achieved par excellence by proton beams. Let us hope that we do not have to live through a whole generation of permutations of IMRT ingenuities and chemotherapy adjuvants until protons, from eventually simpler and cheaper generators, come into their rightful place. Acknowledgements The author thanks Dr Joe O. Deasy, at the Mallinckrodt Inst of Radiology, St Louis, for help with finding certain references to proton therapy, and Dr Rock Mackie for many discussions.
References 1 Cozzi L. A treatment planning comparison of 3D conformal therapy, intensity modulated photon therapy and proton therapy for treatment of advanced head and neck tumours. Radiother Oncol 2001;61:287–297. 2 Zurlo A, Lomax A, Hoess A, et al. The role of proton therapy in the treatment of large irradiation volumes: a comparative planning study of pancreatic and biliary tumors. Int J Radiat Oncol Biol Phys 2000;48:277–288. 3 Webb S, Nahum AE. A model for calculating tumor control probability in radiotherapy including the effects of inhomogeneous distributions of dose and clonogenic cell density. Phys Med Biol 1993;38:653–666. 4 Mackie TR, Balog J, Ruchala K, et al. Tomotherapy. Semin Radiat Oncol 1999;9:108–117. 5 Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose response: results of the M.D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002;53:1097–1105. 6 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;53:1111–1116.
7 Goffman TE, Glatstein E. Intensity-modulated radiotherapy. Rad Res 2002;158:115–117. 8 Joiner MC, Marples B, Lambin P, Short SC, Turesson I. Low-dose hypersensitivity: current status and possible mechanisms. Int J Radiat Oncol Biol Phys 2001;49:379–389. 9 Thames HD, Schultheiss TE, Hendry JH, et al. Can modest escalations of dose be detected as increased tumor control? Int J Radiat Oncol Biol Phys 1992;22:241–246. 10 Okunieff P, Morgan D, Niemierko A, Suit HD. Radiation dose– response of human tumors. Int J Radiat Oncol Biol Phys 1995;32:1227–1237. 11 Levegru¨n S, Jackson A, Zelefsky MJ, et al. Risk group dependence of dose–response for biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer. Radiother Oncol 2002;63:11–26. 12 Suit HD. The Gray Lecture 2001: Coming technical advances in radiation oncology. Int J Radiat Oncol Biol Phys 2002;53:798–809. 13 Brahme A. Dosimetric precision requirements in radiation therapy. Acta Radiol Oncol 1984;23:379–391.
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14 Fowler JF, Chappell R, Ritter M. Is alpha/beta for prostate tumors really low? Int J Radiat Oncol Biol Phys 2001;50:1021–1031. 15 Fowler JF, Ritter MA, Chappell RJ. What hypofractionated protocols should be tested for prostate cancer? Int J Radiat Oncol Biol Phys. (Submitted May 02). 16 Martel MK, Ten Haken RK, Hazuka MB, et al. Estimation of tumour control probability model parameters from 3-D dose distributions of non-small cell lung cancer patients. Lung Cancer 1999;24:31–37. 17 Rosenman JG, Halle JS, Socinski MA et al. High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: technical issues and results of a phase I/II trial. Int J Radiat Oncol Biol Phys 2002;54:348–356. 18 Blomgren H et al. Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Acta Oncol 1995;34:861–870. 19 Fowler JF, Chappell R. Non small cell lung cancers repopulate rapidly during radiation therapy. Int J Radiat Oncol Biol Phys 2000;46:516–517.
What Can we Expect from Dose Escalation Using Proton Beams? J. F. Fowler Department of Human Oncology, Medical School of the University of Wisconsin, Madison, Wisconsin, U.S.A. ABSTRACT: It has been demonstrated without doubt in the literature, including elsewhere in this issue, that much better conformal dose distributions in radiation therapy can be obtained with proton beams than with photons (X-rays) or electrons. It is also clear that this remains entirely true – for the fundamental reason of particle range – even after the latest and projected developments in computer-generated IMRT (intensity-modulated radiation therapy) photon dose escalation are fully considered. We consider several examples of tumour dose–response curves that illustrate the quite large gains to be obtained when dose escalation can be achieved, if normal tissue complications can also be avoided. Two contrasting types of tumour are considered in detail, prostate tumours and non-small-cell lung carcinomas. There is a considerable way to go yet to achieve really high non-recurrence rates, especially in the lung tumours. Proton beams would make this progress much safer and more effective than any variants with photons. Fowler J. F. (2003). Clinical Oncology 15, S10–S15 2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved. Key words: Proton range, intensity-modulated radiation therapy, tumour dose–response, normal tissue complications Received: 2 October 2002
Introduction
‘Dose uniformity in the target and minimization of toxicity in healthy tissues are requirements that, with conventional treatment methods, are often incompatible’ [1]. It is demonstrated in many articles in the literature that protons have the potential to significantly improve current dose distributions [1,2] – even the most advanced forms of IMRT (intensity-modulated radiation therapy). In the present paper we illustrate that the gain in tumour control can be very large, together with much less exposure of normal tissues. First we must emphasize why proton beams are so much more effective than photon beams, and then we shall deal with the corresponding dose–response curves. Early in their development, malignant tumours consist of very few cells and they are well localized. As they develop, they tend to spread to other organs or even, through blood or lymph drainage, to distant organs as metastases. When the disease is confined a local treatment such as surgical excision or radiation therapy is preferable, and the results are often successful. If however regional spread has occurred surgery will not be a good option: chemotherapy with or without radiotherapy is likely to provide a better result. This is where the most recent methods of diagnosis, which are currently being rapidly developed, are very important. Author for correspondence: Dr J. F. Fowler, Department Human Oncology K4/316, 600 Highland Ave, Madison WI 53792, U.S.A. Tel: 608-265-0506 or home: 608-231-5896; Fax: 608-263-9947 or home: 608-231-5897; E-mail: jff[email protected] 0936–6555/03/010S10+06 $30.00/0
Accepted: 17 October 2002
The longer a patient has a viable tumour before diagnosis and treatment, the more likely the tumour is to ‘break out’ as a metastasis, which much reduces the lifespan of a patient. The possibility of such a ‘breakout’ makes local control from a local treatment, such as radiotherapy, vital to achieve. Doses that are slightly too low represent complete failures. Tumour control might be achieved in principle by increasing the radiation dose – but this cannot be done precisely and nonspecifically because the physical properties of photon beams deliver too much dose to surrounding normal tissues. Even the narrowest or sharpest-edged beams of X-rays unavoidably do this, because every beam of photons continues to penetrate through the tumour. Photon beams are attenuated only gradually as they go through any substance. Therefore the photon doses to tissues just behind each tumour are similar to those within the tumour, unless the tumour is very large. The opposite is true of proton beams, which stop completely at a finite range that can be set at the far edge of a target volume. One obvious way of elevating a dose within a tumour volume is to keep a beam of X-rays aimed at the tumour and to revolve the X-ray machine around the tumour, or in alternative geometries to revolve the patient slowly in front of an X-ray machine. This will obviously deliver the highest dose to the tumour whilst spreading out the dose to other tissues all round it. Both these methods have been used, together with non-radial directions that can be delivered with three-dimensional (3D) conformal photon or proton radiotherapy but not with ordinary
2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
step-and-shoot tomotherapy. Within the last few years giant strides have been made in computerized ways of delivering such photon beams, using basically cylindrical shapes of beam-aiming points from outside the patients’ bodies. Such methods are called IMRT because the intensity of the beams is also varied to deliver less radiation when passing through more sensitive parts of the anatomy [3]. A particularly sophisticated form of IMRT is helical tomotherapy where the patient is moved on a couch through the axis of a linear accelerator producing X-rays mounted on a circular frame like a computerized axial tomography (CAT)-scanner. A simultaneous image is continuously recorded of the treatment volume actually being irradiated, so that the treatment could subsequently be altered if desired to compensate for any divergencies in dose or volume [4]. This refinement is called adaptive radiotherapy. All of these advances in delivery of photon (or electron) therapy are already showing improved results in decreased complications, and significantly improving longterm local control when doses have been escalated [5,6]. There are clearly significant gains still to come from using these new methods of photon delivery in certain other disease sites, although not as large as the gains from the use of protons. The total integral dose delivered to a length of say a patient’s trunk comprising the whole volume irradiated by any photon method is not significantly different no matter how ingeniously the beamlets of X-rays are directed. It is much the same as the integral dose delivered from a simple two or four-field box technique. There is still an open question about whether the quite low, but perhaps not negligible, radiation doses which are then being spread over larger volumes of the patients’ anatomies could lead to some untoward effects in future. There have been some basic radiobiological suggestions that this might be so [7,8], but until some definite evidence emerges, the radiation oncology community seems inclined to say ‘that’s just crying wolf’ and to risk the X-ray IMRT strategy. The reason why proton beams are always better at providing treatment dose distributions than photons is both fundamental and simple. Protons beams have a definite range, with negligible ‘spallation’ or forward projection of other particles beyond the end of that range. This is the essential, and very large, advantage that they have over the photons, which are attenuated gradually in tissue and therefore deposit significant doses beyond the target volume. Protons are also better than heavier nuclear particles in this respect of forward projection of spallation. Protons also have the advantage of a build-up of ion density and thus biological effect within a few millimetres of the end of their well-defined track, in the well-known Bragg peak, which helps in achieving the sharpness of the end of their range. The reason why the obviously superior physics of proton beams is not yet employed more widely is the size and expense of proton-generating machines. Of course
S11
dedicated proton generators for cancer treatment would come down in cost as soon as more were manufactured, and they need not be as unwieldy (or inaccessible) as those machines built originally in physics departments. They would be designed with multiple beam portals so that six or eight patients could be treated simultaneously. At present more than 30 proton machines are in use worldwide for cancer treatment or in planning in various countries. These can be read about in the newsletter ‘Particles’, sponsored as a charitable organization by the Particle Therapy Co-Operative Group, produced by their Secretary Dr Janet Sisterson, at the Harvard Cyclotron Laboratory, Massachussetts General Hospital, 30 Fruit Street, Boston, MA 02114, U.S.A. There are also about 20 websites on this topic in various countries. The contrast between doses to normal tissues and higher doses to tumour volumes is much greater with proton beams than with photons. There is no doubt that the protons beams will provide better dose distributions for curative radiotherapy that any present radiotherapy photon techniques. The question seems to be how much better do we need to see it is, before we decide we want it? Although reasonably high levels of local control can be achieved with radiotherapy now in some cancer sites, they fall far short, in all except a few sensitive types or very small tumours, of the 95–100% long-term success rates that can be obtained with combinations of surgery and radiotherapy in early-stage breast cancer or with radiotherapy only in early-stage carcinoma of the cervix.
Materials and Methods
Now that we have explained the basic superiority of protons over photon beams, we can analyse the resulting expected gains in tumour control. There can no longer be any doubt that higher doses in radiotherapy can lead to higher rates of tumour control, (unless local control is already above 90%). However some clinical studies have been too small to show statistical significance, and much is made of these by the nay-sayers. As explained above, the necessary higher photon doses cannot at present be given because of complications in normal tissues, although gradual progress in conformal 3D and IMRT treatments is demonstrating that dose escalation is in principle feasible. As well as two careful and comprehensive studies in the 1990s of many types of tumour [9,10], two recent, very detailed, institutional studies of prostate cancer published in the same recent edition of the Int J Radiat Oncol Biol Phys 2002 [5,6] leave no doubt at all that significant increases in biochemical control of PSA level at 4–5 years after treatment occur with increases in total dose. Further, detailed analyses of one of those studies make it clear that the dose–response curves become steeper when the prognostic factors of subgroups of patients can be characterized in more detail [11]. This means that for any individual patient the gain in tumour effect will be larger than the average
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values obtained from groups of patients, which are the only values that we can determine from clinical results. Dr Herman Suit has also recently summarized these conclusions succinctly in a wide-ranging review of advances in radiotherapy [12]. That paper also made it clear that the most effective way of increasing dose in a tumour target volume whilst minimizing dose in neighbouring normal tissues is to use proton beams. This physical superiority of proton tissue doses is clear [1,2,11,12], in spite of the impressive advances recently made in the delivery of photon beams as referred to above [3,4]. We shall review a selection of dose–response curves in order to gain some insight into the increases of tumour control expected from various dose escalations.
Results and Discussion
The certainty with which an increased of dose in radiotherapy has been associated with increases in local control, and more importantly in progression-free survival, have increased over the last 10 years. In an earlier reference [9], the median specific increase of local control for 17 types of tumour averaged 1.65% per 1% increase of total fractionated dose. In the second early reference [10] 50 values of the slope of tumour dose–response curves were analysed, ranging in slope from 0.3% to 47.3 with a median slope of 1.45% per %. (This is a common way of describing the rate of increase of tumour control with total dose, known as the gamma-50 slope of the dose–response curve [13]. An alternative method is to give the absolute % increase of local control (or survival) per Gray of dose, and discussions about the merits of both methods continue.) Neither method is easily applicable to schedules with different sizes of dose per fraction, which therefore have to be stated. The two values of gamma-50 quoted of 1.4 to 1.65 illustrate that if an increase of 10% in total dose is delivered to a given tumour site, an absolute increase of 14 to 17% can be expected in the corresponding local control (or survival). As will be shown below, this is rather a modest increase of effect, which would require several hundred patients in each of two arms of a clinical trial to demonstrate at the usual level of significance. Reference has been made above to the well known steepening of tumour dose– response curves when sufficient diagnostic or prognostic detail is available to narrow the spread of variables within any one group of patients ([11]; Figs 4 and 5 where the gamma 50 values for three discrete ranges of prostate cancer risk range from 4.6–5.2, being much sharper than the values of 1.4–1.65 mentioned above). By such means – and prognostic factors are being discovered at an increasing rate – the steepness of tumour response curves can be expected to increase in the future. There has however been no doubt from the earliest days that sizeable clinical trials are necessary to determine that a clinical increase in local control reaches this level of significance. From the modest slopes mentioned
above, a 10% increase of dose at the tumour would yield a 14 (or 17)% increase in local control, which requires about 250 (or 175) patients at each of two dose levels, a total of 500 (or 350) patients in all. An increase in dose of 20% (or the equivalent in biological effect) requires about 130 patients in each group, a total of 260 in all. It is easy to see that a modest increase of only 10% in local control, or whatever endpoint is determined, would require two groups of patients of about 500 in each, or 1000 in all. But we may look forward to steeper dose–response curves in future as explained above.
Prostate Tumour Dose Escalation
We shall take two types of tumour as representing two extremes of the spectrum of difficulty in effecting a long-term cure of cancer. The first example is that of prostate cancer, that has now replaced lung cancer as the commonest male cancer. It is for this type of tumour that the recent examples of relative success in long-term cure (no increase in PSA at 4–5 years) have been reported for escalation of total dose from 70 to 78 Gy [5] and from 66 to 81 or 86.4 Gy [6]. We modelled Fig. 1 from the available published data for survival of patients without recurrence of PSA at 4–5 years from five well known prostate treatment centres, with 10 dose levels of external 3D conformal or IMRT beams [14]. The resulting logistic regression curve is shown, having a TCD50 of 66 Gy (in 2 Gy fractions, that is, normalized total doses NTD) and a gamma-50 slope of 2.1. Since not all the centres used doses of 2 Gy (range 1.8–2.2 Gy), the total doses were normalized using the value of alpha/beta=1.5 Gy for prostate tumours which we determined in the same paper [14]. This was a small correction as described in that paper. We have subsequently used this regression curve to predict the increases in bNED when various amounts of dose escalations were modelled. It is well known that slowly proliferating normal tissues in which late complications occur have a high sensitivity to altered dose per fraction, which means that they have small alpha/beta ratios, indicating large capacities for repair between fractions (beta in the Linear Quadratic formula) compared with their intrinsic radiosensitivities (alpha). The same trend applies to malignant cells in tumours [14]. Because prostate malignancies are unique among tumours in proliferating slowly, and therefore in having very low values of the ratio alpha/beta, they enable a special advantage to be obtained from the use of larger doses per fraction, called hypofractionation. The outstanding conclusion was that hypofractionation (with a carefully calculated reduction of total dose assuming alpha/beta=3 Gy to maintain constant late rectal effects) could give very large increases of bNED, with no increase of rectal complications. For example changing from 36 fractions of 2 Gy to 15 fractions of 3.6 Gy gave a predicted increase from 69 to 85% bNED at 5 years. Further hypofractionation to 10 fractions of
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Fig. 1 – Logit regression curve of biochemical no evidence of disease (PSA) at 4–5 years after external beam treatment from the five treatment centres referenced in Ref. [14]. The abbreviations in this figure’s key are in sequence Alabama, Fox Chase Cancer Center, William Beaumont Hospital, Memorial Sloan Kettering Institute, and the MD Anderson Cancer Center. This dose–response curve is discussed further in Ref. [14] together with the definition used of intermediate risk. Reproduced with permission of the publishers of Int J Radiat Oncol Biol Phys from Ref [14].
4.7 Gy would increase the predicted bNED to 90%, all with no increase in rectal complications [15]. While this should be quite possible with existing X-ray technology, (because the dose to cure 50% of prostate tumours is only about 66 Gy in 2 Gy fractions), it would be easier and require simpler treatment planning with proton beams. Levegru¨n et al. [11] in analysing their own data from the Sloan Kettering Institute obtained much steeper curves with gamma 50 values of 4.6 to 5.2, presumably from the smaller variations in a single institute study. These data suggest that it might be even easier to achieve such gains, approaching 100% bNED with suitable dose escalation, even for intermediate risk prostate tumours. The use of proton beams will eventually be required to achieve those maximal results.
Non-Small-Cell Lung Cancer (NSCLC) Dose Escalation
The second example is non-small-cell lung cancer (NSCLC), which is increasingly being diagnosed by spiral CT imaging as early-stage small tumours. The results of a carefully conducted clinical trial of photon dose escalation by the University of Michigan at Ann Arbor were published by Martel et al. [16]. Doses were given at 2 Gy per day five times a week so that 90 Gy required 9 weeks of radiotherapy. The characteristics of the curve for the survival of patients without tumour progression at 30 months were given as TCD50=84.5 Gy with a gamma-50 slope of 1.5 [16]. This curve is traced in Fig. 2, and the striking difference from the curve for prostate tumours is clear. The dose to
‘cure’ 50% of lung tumours was 84 Gy, which is 18 Gy or nearly 30% higher than for the prostate tumours, and that makes an enormous difference. This might be a reflection of the fact that most lung tumours are much larger, even at diagnosis, than the prostate tumours, which are currently detected by the serum marker PSA. Second the dose–response curve for NSCLC is flatter than that for prostate tumours. This is likely to be a reflection of a larger range in size at treatment of the lung tumours. The practical conclusion is that even at a dose of 70 Gy (in one or two X-ray fractions per day), no more than about 20–25% disease-free survival at 30 months is expected for patients with NSCLC. This is indeed about the best that any photon radiotherapy can do at present. Doses less than 70 Gy give correspondingly more depressing results, and failure to eliminate the primary tumour is an open invitation to metastasis. Examples of slightly better results from slightly higher doses (plus chemotherapy) are given recently by Rosenman et al. [17]. The case for higher doses is very clear, as the Ann Arbor results have demonstrated, but normal tissue damage, especially pneumonitis, prevents it, except in the special case of selected small volumes as in the pioneering study at Ann Arbor, where they have been able to go up to 103 Gy for the smallest volumes irradiated. They reported one recurrence at 90 Gy out of three patients, which is not surprising because the curve in Fig. 2 does not predict more than about 60% local control at that dose. This is a situation where dose escalation, using the photon-specific IMRT method of spreading dose out widely around the tumour, that is, shared between much
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there is no alpha/beta (slow proliferation) advantage for the fast-growing lung tumours as there is in the slowgrowing prostate tumours. The ‘stereotactic ablation’ of lung tumours is being experimented with, but it will be very much easier and safer to use proton beams, with their much lower spreading of dose among many other tissues, at about half the spread with photons.
Conclusions
Fig. 2 – Logit regression curve for survival without disease progression at 30 months in non-small-cell lung cancer, reconstructed from the parameters quoted by Martel et al. in Ref. [16]. Their actual clinical data had been accumulated up to about the TCD50 dose level at that time. Reproduced with permission from the publishers of Int J Radiat Oncol Biol Phys, in part from Mehta M, Scrimger R, Mackie R. et al. ‘A new approach to dose escalation in non-small-cell lung cancer’. Int J Radiat Oncol Biol Phys 2001;49:23–33.
larger volumes of lung which each receive smaller doses per unit volume, cannot work well. That is because the limiting dose to lung is correlated with the mean lung dose. The smaller doses that spread away from the target volume in 3D conformal therapy are here deleterious. As explained in the introduction, the integral photon dose to a whole trunk is fairly independent of how it is spread out within the trunk, so concentrating the dose in the target at the expense of much larger volumes given lower doses is not likely to work in this disease site. It was only possible in the Ann Arbor dose escalation studies in those tumours which were very small and which required very small target volumes. An extension of such studies originated in Stockholm from brain stereotactic irradiations [18]. It is being pursued in Japan and in Indianapolis, U.S.A. where small tumours and small volumes of lung can be selected for stereotactic irradiation, with a volume limitation that we are still learning about, possibly related to the unusually rapid rate of fall-off with dose outside the small stereotactic fields. A further problem with conventional dose escalation is that 100 Gy (to an appropriately small volume) would take 10 weeks to administer, and yet NSCLC tumours proliferate rather fast, almost as fast as head and neck tumours [19]. Hypofractionation might reduce overall times by a few weeks, but the large doses per fraction mentioned in the context of prostate tumours above are not permissible, because
There are now several examples of dose escalation which demonstrate that local control and survival can be significantly increased if higher doses are used [5,6,11,12,17]. There are other examples where the use of radiotherapy with or without surgery has reduced recurrences to less than 10%, especially in cancer that can be detected early by new techniques. A study of dose–response curves in other sites shows that there is a considerable way to go in achieving sufficiently high doses to reach these levels of success. Improvements are taking place, but they taking place very slowly. One of the surest ways of improving tumour control is by delivering adequate radiation dose, as illustrated above; but normal tissue damage must not be increased. The avoidance of normal tissue dose is achieved par excellence by proton beams. Let us hope that we do not have to live through a whole generation of permutations of IMRT ingenuities and chemotherapy adjuvants until protons, from eventually simpler and cheaper generators, come into their rightful place. Acknowledgements The author thanks Dr Joe O. Deasy, at the Mallinckrodt Inst of Radiology, St Louis, for help with finding certain references to proton therapy, and Dr Rock Mackie for many discussions.
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