Intensity-Modulated Radiation Therapy: The Inverse, the Converse, and the Perverse

Eli Glatstein
Intensity-modulated radiation therapy (IMRT) is a refinement of current radiotherapy techniques rather than a major breakthrough. The term IMRT includes several different techniques that all share with classical arc therapy the principle of using multiple fields to reduce the dose to normal tissues, but integrating to a higher dose throughout the tumor volume itself. This paper reviews not only the putative upside but also the downside of the development of IMRT. Theoretical, practical, and cost considerations, both positive and negative, are discussed. There are several issues to be considered, but the most important perversely predict a significant increase in radiation-induced neoplasms, resulting not only from larger volumes of tissue exposed to more modest but still mutagenic doses, but also from a significant increase in total body dose from leakage, because the beam is typically on for a considerably longer period of time than is conventional. A plea is made for radiation oncologists to maintain a strong biologic and cellular orientation as oncology rapidly becomes more molecular in its orientation. Copyright 2002, Elsevier Science (USA). All rights reserved.

What

is aught, but as 'tis valued? --Troilus and Cressida, William Shakespeare

T modulated radiation therapy (IMRT) is difficult to dissect. IMRT has been heavily touted by both vendors and investigators, although actual clinical data for analysis have so far been sparse. Media present the subject as a major "breakthrough" in treatment, largely by demonstrating the technology itself as a virtual hypnotic. Yet definitive evidence of true improvement in outcome is presently lacking. It is important to acknowledge that because the design of these new technologies represents a major investment of time and effort by vendors, they are likely here to stay; they represent the way that things will be done in the future. They certainly decrease manual efforts of therapists. Moreover, there is no doubt that some patients will benefit. The real question is what quantitative proportion of the patient load will truly benefit beyond the accomplishments of "conventional" treatment; conversely, what proportion of patients might actually be harmed by IMRT? Though several papers claim to show improvements in the planned dose distribution, the fundamental question is whether these arbitrarily defined, "improved" distributions on paper will

he present euphoria surrounding intensity-

From the Department of Radiation Oncology, University of Pennsylvania Medical Center, Philadelphia, PA. Copyright 2002, Elsevier Science (USA). All rights reserved. 1053-4296/02/1203-0009535.00/0 doi:10.1053/srao.2002.32433

translate into meaningful improvements in measured outcomes among patients. These technologies are really refinements of classic linear accelerator-based radiation therapy, not breakthroughs. There is no revolution in the creation of photons or alterations of their characteristics; rather, the refinement is in the means of delivering radiation to the target. Moreover, it should be recognized that three-dimensional (3D) planning programs are actually based on a stack of 2D CT scans, which has been in use for over 20 years. No new patient or tumor data are actually generated, although digitally reconstructed radiographs (DRRs), beam's-eye views (BEVs), dose-volume histograms (DVHs), and third dimensions of the image are today demonstrable on screen. These features are clearly helpful, but none can truly be described as critically important. This review begins with the assumption that "there is no free lunch." All new developments have a downside, as well as an upside. A focus on both facets of this technology is the thrust of this commentary, which is organized along the lines of theoretical, practical, and cost considerations o f l M R T (Table 1). It is important that both sides of the IMRT issue be discussed openly, because some of the downside implications have so far received little attention among physicians. It should also be emphasized that a variety of types of treatments belong under the broad heading of IMRT, which includes a series of technologies that are still developing. Some would define static multileaf collimation (the step and shoot technique) as IMRT. Others might restrict it to "dynamic multileaff' collimated IMRT, in which

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Table 1. Intensity-Modulated Radiation Therapy

Positive Theoretical Considerations Negative

1. Permits dose escalation, which may improve local control

2. May have impact by differential dose rates

1. With increased volume exposure to modest doses, an increase in radiation-induced cancers may
Occur

9. Matching and penumbra effects of small voxels at target (ie, hot and cold spots)

Practical Considerations

3. Reduces morbidity compared to conventional doses (without considering impact of dose escalation), especially in children 4. Can approach any complex problem, regardless of shape, to "optimize" dose distribution 5. encourages those who use low doses to elevate doses to appropriate level

3. Voluntary and involuntary movement at most sites confounds dose calculations and DVH interpretations 4. Major problems remain in imaging the extent of cancer 5. Significant increase in TBI to patients (and potentially to technicians) from increased beamon time and leakage from machine head 6. Neutron contamination to TBI dose if performed at high energies ( -->15 mV) 7. Very tight margins introduce uncertainty in peripheral target dose and predispose to marginal misses 8. Inability at present to validate fields/ports in vivo 9. Complexity breeds increased opportunities for errors
Cost Considerations

6. Reimbursement is presently generous

10. Expensive in space, time, manpower, and dollars 11. Motorized multileaf collimator yields greater downtime and increased repairs 12. Potentially undercuts perception of radiation oncologist as physician and creates impression that he/she is mere technician

the g a n t r y arcs a n d the leaves move in a n d out of t r e a t m e n t on a c o n t i n u a l basis. Still o t h e r s m i g h t define I M R T as a s e g m e n t e d , inverse t r e a t m e n t p l a n n i n g m e t h o d ; o t h e r s m i g h t hold to a definition of forward t r e a t m e n t p l a n n i n g , with a variety of r e s t r i c t i o n s p l a c e d on dose d i s t r i b u t i o n t h a t r e q u i r e an o p t i m i z a t i o n o f the t r e a t m e n t plan, a l t h o u g h e x a c t l y w h a t an " o p t i m i z e d " t r e a t m e n t p l a n m e a n s is, to some d e g r e e , in the eye of the b e h o l d e r . Still a n o t h e r form of I M R T would be t o m o t h e r a p y , 1 which is still in its infancy'. All of these forms of I M R T are p r e d i c a t e d on some modification of e x p o s u r e as a s e l e c t e d function over time. In addition, it is true t h a t , in a very p r a c t i c a l sense, t r a d i t i o n a l t r e a t m e n t with full c o m p e n s a t i n g filters also r e p r e s e n t s a form o f i n t e n s i t y - m o d u l a t e d t r e a t m e n t 2 in t h a t the dose

of r a d i a t i o n is modified at the t a r g e t level, but not on the basis of t i m e variations; however, this form is not p a r t of the e n s u i n g discussion. A d e t a i l e d t e c h n i c a l d e s c r i p t i o n of each of t h e s e various options is b e y o n d the scope of this p a p e r . T h e p o i n t to e m p h a s i z e is t h a t the r e a d e r needs an a w a r e n e s s o f the r a n g e o f options u n d e r the h e a d i n g of " I M R T . " M o r e o v e r , he or she n e e d s to be a w a r e t h a t some of t h e issues ( p a r t i c u l a r l y u n d e r the h e a d i n g of p r a c t i c a l c o n s i d e r a t i o n s ) will not a p p l y equally to all of the v a r i a n t s of I M R T , a l t h o u g h most of t h e m do.

Background
Because r a d i a t i o n t h e r a p y is e s s e n t i a l l y a physical solution to w h a t is a biological p r o b l e m , it will

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never

be the entire answer to the problem of cancer therapy. Yet it remains an important component of the answers. A local t r e a t m e n t is best assessed for efficacy by probabilities of local control. But it must be acknowledged that any local control that ends with death within 12 months of t r e a t m e n t nmst be interpreted as having a limited practical meaning. Moreover, cancer patients typically develop metastases; and when they do so hematogenously, generally they are incurable. Our main goal is more and better survival; thus, it is important not to focus exclusively on local control simply because, as radiation oncologists, we would prefer not to discuss poor survival of certain patient groups. Overall survival remains the most important p a r a m e t e r of successful treatment, which is the reason why combined modality t r e a t m e n t has become so important to the development of oncology in general; conceptually, it addresses both local and disseminated disease. The basis of I M R T is the idea of spreading the dose around, so that larger volumes of normal tissue are generally exposed to more modest doses of radiation, but the doses integrate into a higher total dose throughout the volume of the tumor itself. The principle is identical to that of traditional arc therapy, albeit I M R T can be planned for noncoplanar treatments. Arc therapy has long been an important component of radiation therapy, but classic arc therapy seems to have fallen into relative disuse in recent years, presumably due to a decline in confidence that is both unsubstantiated and inexplicable; dynamic IMRT may eventually rejuvenate interest in this form of treatment. The value of spreading the smaller doses over larger volumes figures to be especially important in children, whose normal tissues are still undergoing growth and development3; conversely, a serious consequence of this spreading of dose over larger volumes predisposes to a significant increase in frequency of radiation-related oncogenesis (see below).

A
100'
~176 ~

%
TL~zllt~r Local Control ~ .,'~onnal

50

Contrt,I

." Ti.~ue

Dose

B
100'
.. . . . . . . . . . . . . . . N++mml .'~ "+ Tumor Cnnm,l

%
Local Control

50'

Dose

Figure 1. (A) A theoretical diagram of normal tissue

injury and local control as functions of increasing dose in linear scale. The curves are conveniently drawn as steep and parallel. (B) More realistic portrayal of normal tissue injury and local control as functions of dose in the clinical setting. The curves are not parallel with less steep tumor control.

Theoretical Considerations
Positive
Much of the euphoria concerning I M R T results from a corollary principle of dose escalation, often implied within the term IMRT. The basis of enthusiasm for escalating doses results from the

fact that, theoretically, there should be some associated improvement in local control with increasing doses; the question remains how much? Textbooks have routinely included theoretical diagrams on linear scales showing a sigmoid dose response for both tumor and normal tissue, where the curves are both steeply drawn, running parallel to each other (Fig 1A). Perhaps this is true for seminomas, but these are atypical in terms of their exquisite radiosensitivity. The sensitivity for most neoplasms cannot be expected to parallel normal tissue, because in practical terms, normal tissues are devoid of mutations, whereas neoplasms represent a cascade of mutations. Therefore, neoplastic sensitivity to irradiation figures to be much more heterogeneous. Thus, the slope of the sigmoid curve representing tumor can be logically predicted to be much less steep than that of normal tissues (Fig 1B). T h a t is what is actually seen in the clinic, and it does not even account for known influential factors of

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histology, tumor mass, cell kinetics, oxygen and nutritional status, and a host of molecular parameters that are only beginning to be understood at this time. Moreover, a randomized study has already demonstrated that survival gains to be made from dose escalation in patients with unresectable lung cancer are both modest and limited. 4 Finally, there have already been randomized studies in breast, lung, and rectal cancer, in which, following a complete surgical resection, radiation therapy markedly improved local control without any noticeable impact on survivah 5-7 It is simply erroneous to presume that continuous dose escalation means progressively greater survival. The second positive theoretical consideration relates to dose rate. One of the advances of using more than two fields and integrating to high dose is that the dose achieved at the tumor effectively gives a higher daily dose rate to tumor than to surrounding normal tissues coincidentally treated, a,9 in contrast to what is achieved with traditional parallel, opposed fields. By treating the tumor at a daily dose of 200-250 tad while keeping the dose to normal tissues closer to 150180 rad, there may well be some differential benefit to be achieved. The dose-rate issue has not received much attention as such, but effectively it means that on a routine basis, patients could receive accelerated fractionation to tumor, which may overcome the problem of accelerated repopulation in some tumors. 1~ Although survival benefits of such t r e a t m e n t may not be huge, hyperfractionation studies in head and neck cancer ~ already suggest that there will be some modest benefit in outcome by such exploitation of differential daily dose rates and accelerated fractionation.

Negative
On the other hand, although the functional results of normal tissues may he improved by such maneuvers, the process of mutation itself is a direct reflection of ionization that takes place in tissues. If larger volumes of normal tissues are exposed to modest doses, the greater numbers of exposed cells mean that the likelihood of mutation is predictably greater as a result of treatment. Moreover, it has long been known that lower doses are actually more oncogenic than higher doses in mice. ~2 This paradox results from

an exponentially increasing mutation rate with dose, whereas the proliferative capacity of cells decreases exponentially with dose as cells are killed. The net result is a bell-shaped curve in which the peak of mutation is not expressed at the highest doses, but rather at an intermediate level, though the precise location of the peak is unclear. 13 H u m a n data on this point are difficult to come by; in a retrospective case-control study of children irradiated for cancer, treatment-induced bony sarcomas appeared to increase with tumor dose, j4 but those children received extensive chemotherapy to further confound interpretation. Moreover, there was no analysis to calculate dose in the area of the second cancer itself, to see if those induced neoplasms occurred in the region of penumbra. At present it seems most reasonable to assume that humans will prove to be similar to other m a m m a l s in terms of radiation-induced oncogenesis. It is essential that this issue be followed closely in the follow-up clinic. Another serious theoretical problem with I M R T is the ability to match segmental exposures at the target level. If small segments are treated, then they will presumably have some imperfection in matching to the adjacent segments laterally, superiorly, or inferiorly. On the other hand, the discrepancies will likely be smeared out over time by fractionating these exposures. However, the smaller the segment being exposed, the greater the issues of penumbra, and hence uncertainty and inhomogeneity of dose, become at depth. By adding any degree of movement 15 that takes place within the patient, calculations truly become variable and quite uncertain in terms of the exact dose received by the tumor itself, especially peripherally, if margins are "tight." Also, leakage through the m u h i l e a f collimator has been described as 4%. 16 However, when multiple fields are involved, the leakage problem will also integrate to greater numbers and further compound the dose inhomogeneity. Perhaps homogeneity of dose, as we have thought of it traditionally in radiation oncology, is less important ~7 than we have been taught; but that remains to be seen. Another consideration is the distinct possibility that the "bystander effect" may be extremely important in clinical radiation therapy, as has been demonstrated by Sauvant et al in elegant tissue culture experiments. ~8

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Practical Considerations

Positive
There are already data suggesting that, with standard dosage using CT planning for a definition of tumor volume and slowing down the dose rate in normal tissues that surround the tumor volume, serious grade 3 or greater acute morbidity appears to be decreased.<9,*9 The long-term morbidity remains to be defined, inasmuch as it takes many years to establish with certainty what tissues can truly tolerate, especially neurologic and vascular tissues2 ~ 99 Focusing on complications overlooks the fact that radiation-induced morbidities have markedly declined from those of 30 years ago. The primary reasons for this decline in injury are related to better fractionation (ie, treating all fields each day), better localization of the target volume by utilizing both formal simulation and especially CT, and use of multiple energies (both photon and electron) that permit mixing and matching of energies with individual patient characteristics. However, there is always concern that if dose escalation is built into the IMRT plan, the resulting long-term morbidities could negate some or even all of the presumed benefits from IMRT obtained in terms of local control. Probably the most attractive feature of IMRT is that it can approach any complex problem, regardless of shape, with an enhanced ability to optimize the dose distribution. The definition of "optimal" is somewhat variable from patient to patient, physicist to physicist, and physician to physician; but it is clear that one can deposit the radiation in the form of any concave distribution, even a completely circular one, by using an inverse planning system. 8 This flexibility has great appeal for the occasional complex problem that up to now has been treated with multiple fields, complicated weightings, and sophisticated blocking systems on an ad hoc basis. With IMRT, one can systematically devise a plan whereby the radiation dose distribution can correspond to virtually any irregular shape. That certainly has some attraction, although it is entirely unclear whether the putative improvements in paper plans described in many recent publications will translate into any measurable improvement in patient outcomes.

The final positive practical consideration is that the IMRT principles will encourage those radiation oncologists who have previously tended to use low doses in the t r e a t m e n t of malignant diseases to escalate their doses to a more appropriate level. Whether they will go up as high as some researchers have advocated remains to be seen, however.

Negative
Probably the most challenging aspect of I M R T is movement, 15 which continues to be a nagging problem for virtually every patient. Some of the movement is involuntary, and some is voluntary, but the movements that occur will continue to confound (1) calculations of dose, (2) adequacies of arbitrarily defined margins that do not account for movement or for invasive characteristics of specific tumor types, and (3) interpretations of dose-volume histograms (DVH). It is all well and good to show a sharp instantaneous falloff in terms o f a DVH, but what does it truly mean when the target or organ in question moves a couple of centimeters or more? As a consequence of today's precision in treatment, much more attention needs to be focused on immobilization techniques and fundamental positioning of patients. Is every patient best treated in a recumbent position? One of the concerns about basing the plan on an instant "snapshot" of a C T image is that significant respiratory motion classically seen at fluoroscopic simulation may not be taken into account. Often, the physician planning t r e a t m e n t on the basis of the CT snapshot image is mesmerized into thinking that he or she knows exactly where the tumor is, even though it moves 2 cm or more on fluoroscopy, thereby illustrating that virtual reality is not reality. If I M R T had somehow preceded fluoroscopy in development, would we now be enthusiastically extolling the ability of fluoroscopy to image in real time? Efforts are presently ongoing to gate radiation exposure to respiratory movement, in an effort to decrease the amount of pulmonary volume irradiated, and hence decrease the probabilities of radiation pneumonitis. O f course, other things besides dose and volume have an impact on the probability of developing radiation pneumonitis, for example, medication, coexistent medical diseases, smoking history, baseline pulmonary func-

Intensity-Modulated Radiation Therapy

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tion, performance status, and transforming growth factor t3-1,2~ t o name a few. How much can be gained by gating to respiration? It has already been suggested that systematic setup errors are more important. 25 If we really want to minimize lung tissue exposure to radiation, easily the most important single manipulation would be to treat the patient upright, allowing gravity to work to our advantage. 26 When a patient lies down, the diaphragms move upward and the thoracic cavity volume is decreased, which results from decrease in lung volume, not tumor volume. As a consequence, when a patient is recumbent, the ratio of pulmonary parenchymal cells being irradiated compared to the tumor target volume will ahvays be greater than would be the case if the patient were upright. Furthermore, some mediastinal tumors significantly expand in volume when the patient lies down, due to changes in vascular pressures related to the recumbent position. 26 O f course, computed tomography (CT) scanners were not designed to scan the patient upright. Nonetheless, upright CT scanning has been achieved at Fermilab; where necessary, sophisticated t r e a t m e n t planning had to be done in an upright position (personal communication) because the neutron beam at Fermilab is a fixed horizontal beam. Thus, there is more than one possible way to decrease pulmonary injury as a result of irradiating lung cancer. In addition, CT planning still has significant limitations in being able to image the true extent of the cancer; after all, the essential problem of radiation oncology is to know where the radiation needs to be deposited, including draining lymphatics that may harbor tumor cells, with or without enlargement of nodes. We know that tumors have microscopic "fingers" extending outward from the main tumor mass, which simply are not seen, even with modern imaging. For most cancers, the accuracy of CT and magnetic resonance imaging (MRI) compared to true surgical findings is only about 65% to 75%. 27,28 Obviously, this is much better than it used to be, before such technologies were available, but results are still far from ideal. Positron emission tomography (PET) scanning may offer some improvement, 29 but the resolution is still suboptimal. In patients with unresectable lung cancer, some have begun to use PET and CT to restrict the target volume to only that image defined as positively involved,

in an effort to escalate doses safely by decreasing the "standard" volume of treatment; it is noteworthy that only about two thirds of the patients actually received the high doses intended for them 3~ as part of a dose escalation study intending to treat only involved mediastinal nodes. Because lung cancer has the greatest predilection to spread of all the common solid tumors, the wisdom of this approach for lung cancer at this time remains to be seen. Certainly, at the moment, convincing data of improved long-term survival, or even long-term local control (ie, 5-year figures) resulting from such a strategy are lacking. Early reports of dose escalation with this strategy suggest little in the way of mediastinal nodal recurrence or persistence. 3~ But how can one tell for certain that nodal control was actually achieved? In today's world, autopsy data are very uncommon; metastatic expression (coming from sonle source, possibly mediastinal) frequently tends to overshadow assessment of local control, especially if the patient has shifted to a different (ie, medical oncology) clinic. Finally, the old trial of breast cancer from King's College in Great Britain 32 calls into question exactly what defines malignant nodal disease, both clinically and radiologically, when the only discriminator is an arbitrary size cutoff. As implied earlier, survival is the critical end point; surrogate end points are of far lesser importance. Another serious downside to IMRT is a significant increase in total body irradiation (TBI) dose to patients (and potentially to therapy technicians), 33-35 resulting from the beam typically being on for much longer periods of time (3- to 5-fold or more) for IMRT than conventional methods (especially true for inverse planning systems). As a consequence of that increased beam-on time, there will be significantly greater radiation leakage from the machine head, yielding a greater TBI exposure. For some machines, there may be additional radiation resulting from a "pause" state of the machine, due to "dark current." This dark current radiation is nearly 7 times greater than traditional leakage radiation. 36 Moreover, if one were to plan IMRT with high energies of 15 mV or greater, there figures to be a whole-body neutron contamination dose within that TBI dose, 37 with even greater biologic (ie, mutagenic) effects. Greater shielding could conceivably reduce (but not eliminate) this problem but at a cost of considerable increase in

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machine weight and expense. O f course, there is really no advantage to using high energies (>6 mV) for IMRT because, by using multiple fields, the greater exit dose from the higher photon energies effectively negates some of the potential dosimetric advantages. The significance of this greater whole-body dose is a predictable increase in radiation-induced neoplasms, especially leukemia, above present rates. Traditionally, radiation oncologists have accepted as radiation-induced cancers only those within the radiation field. However, if the TBI dose were increased by a factor of 3 (or more), this may no longer be a fair or realistic definition. The TBI increase is real; confirmation of increased, treatment-related leukemia and other cancers awaits careful long-term documentation among those patients who survive complex treatment such as IMRT. The very tight margins that have often been advocated arbitrarily to decrease treatment volumes to escalate tumor doses introduce an uncertainty in the peripheral target dose, especially if there is any movement, which can greatly alter the dose calculation; in addition, such tight margins probably predispose to marginal misses (especially for sarcomas and esophageal cancers). This remains to be seen, but it certainly bears watching. A subset analysis of patients with prostate cancer treated with conformal technique has suggested that modest increase in doses may yield significant improvement in local control and possible cure for those with an intermediate risk, 38 though impact on both higher and lower risk patients was not seen, and follow-up is still preliminary. However, the reader is strongly cautioned not to extrapolate to other sites on the basis of these data, because (1) today, T1 prostate patients are diagnosed early by prostatespecific antigen (PSA) levels only, with no palpable disease (ie, a major shift in lead time from diagnosis), and (2) the relatively thick prostatic capsule is unrepresentative of most primary sites. A combination of absent palpable disease and a thick capsule strongly implies that the risks of lymphatic and hematogenous metastases are lower in such patients compared to such risks associated with carcinomas diagnosed at most other primary sites. Furthermore, if the intention is simply to maximize dose to the prostate, surely, a combination of external radiation plus brachy-

therapy, will achieve doses well beyond what can be delivered by any plan with external beam alone, as has been standard for decades in the management of cervical cancer. Still another present drawback to IMRT is a major inability to validate or verify fields and ports in vivo. One can confirm by means of phantom measurements, but most of us do not treat phantoms. We treat living, scratching, wiggling, breathing, moving (and even occasionally complaining) patients. Who among us, through weekly port films, has not had the experience of recognizing a significant shift (1 cm or more) in a patient during a course of treatment, resulting from unexplained reasons? It remains to be seen if newly designed rapid portal imaging systems can keep up with the fluence of the IMRT in real time.39, 4~ Nonetheless, at the moment, this is still an important area in which IMRT lags behind other conformal approaches. Potential medical/ legal implications are obvious. Finally, it is clear that as the degree of complexity mounts, it breeds an increase in opportunities for errors within the treatment room itself. Although some might argue that computerization will eliminate such errors, anyone who has ever had to correct a computerized bank or credit card statement will have serious doubts about total trust in computer infallibility.

Cost Considerations

Positive
Obviously, vendors have vested interest, hut there can be little question that IMRT is presently being driven at the physician level largely by marketing forces and reimbursement issues. However, it is doubtful that the presently generous reimbursement scale will continue, unless clearly convincing and unequivocal data on improved outcomes can be shown.

Negative
It should be obvious to all that IMRT is expensive in terms of (1) the space, hardware, and software that are required; (2) the time involved in preparation of plans and execution of treatment; (c) the manpower available to carry out such planning and treatment; and (4) the expenditures that go along with all those resources.

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The multileaf collimators, simply because of their motorized use, will probably yield increases in downtime, repairs, and deterioration from usage, although, being purely mechanical issues, these should ultimately prove to be relatively minor concerns. Finally, there is the major concern that as radiation oncologists become more involved with issues of dose distribution and focus their attention on that component of clinical care, they will be perceived less as physicians and more as mere technicians by both patients and other physicians. That particular outcome would be most unfortunate if it were ultimately to decrease the independence of the radiation oncologist.

Conclusions
There is a true need to quantify objectively tile improvement in outcome that can be achieved from IMRT, in direct comparison to other conformal approaches to treatment. If we assume that half our patients are being treated for palliation, it is difficult to see how that group of patients will obtain any substantive benefit. O f the remaining 50%, probably more than 30% of patients are controlled now using conventional doses and treatment, largely in the adjuvant setting, where there is no residual tumor volume; they will not be cured twice. Thus, the true gains that can be logically predicted in terms of survival will be fewer than 20% of the overall patient load. Given that some of those patients have high-grade glioma, pancreatic cancer, and simply large, unresectable, unfavorable cancers of a wide variety, it is probably optimistic to assume that half of that 20% will actually achieve a benefit in survival. If that were to be achieved, it would be a major accomplishment. A more realistic guess would be 5 out of the 20%. A real fear is that it would be only 1% or 2%. Concerning the expenditure involved, such a modest benefit would not be easy to justify to health care policymakers. O f course, such a discussion overlooks the issues of normal tissue injury. As stated earlier, normal tissue injury from a variety of sources has markedly decreased over the last 30 years. The essential point to emphasize is that it is an uncommon event today for a patient to require hospitalization for radiation injury. The benefits of decreasing side effects are certainly laudable but they, too, need quantification. Offsetting a

decrease in side effects are potentially perverse sequelae that are likely to occur in the form of treatment-related cancers (especially leukemia). Such events are most likely to occur in patients with relatively favorable cancers (eg, breast cancer, among others), who can be expected to survive. As noted earlier, these treatment-related cancers can be predicted to become significantly more frequent with I M R T than what has been traditionally identified. Thus, the use of I M R T in patients with a favorable prognosis should not go unchallenged. ]'here are clearly some potential benefits to be obtained from IMRT, but there is a major need to test IMRT objectively against conformal treatment approaches at several different sites, and to assess accurately the gains and sequelae obtainable by means of this new technology, rather than simply touting its presumed advantages and simultaneously neglecting to address its potential pitfalls. As a specialty, we must get beyond assuming that "improvements" in dose distribution on paper plans necessarily imply improvement in patient outcome. That radiation oncology has thus far failed to test IMRT but has simply embraced the new technology, without asking critically substantive questions about its true objective value, does not speak well for the field as a vibrant clinical specialty. The concreteness of IMRT technology unfortunately overshadows the greater gains to be obtained at this time from biologic and combined modality treatments. The greatest future gains in survival will be obtained through better systemic m a n a g e m e n t , simply because that is where success is poorest today. Paradoxically, there will still be major need to obtain local control, in order to see the true long-term benefits of some of these newer biologic efforts. If we had a truly effective radiation sensitizer in the clinic, based either on biochemistry or molecular biology, 42 it would provide greater benefit to patient outcome than all the dosimetric fine-tuning presently under way. Radiation oncologists need to maintain a strong biologic and cellular orientation. Failure to do so will almost certainly herald a decline of our field within an oncologic world that is rapidly changing to a molecular orientation. We must keep pace with these changes and also recognize that any noteworthy increase in radiation-induced neoplasms could ultimately generate a major backlash in patient referrals.

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Eli Glatstein

Acknowledgments Many thanks Schnell, Indra McKenna for feedback, and manuscript. References
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to Drs. Mark Langer, Michael Das, Rex Cheung, and Gillies critical but always constructive to Pat Johnston for typing the

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