- Email: [email protected]
The Clinical Application of Intensity-Modulated Radiation Therapy
The Clinical Application of Intensity-Modulated Radiation Therapy Randall K. Ten Haken, PhD, and Theodore S. Lawrence MD, PhD Intensity-modulated radiation therapy is a delivery system that, when coupled with a treatment-planning optimization system, presents the opportunity to conform the dose to the target better than 3-dimensional conformal therapy, particularly in the case of concave targets. Appropriate clinical applications of this technology to challenging patient treatment scenarios requires careful consideration of issues related to target volume-dose heterogeneity and the influence of patient setup uncertainties. These issues are reviewed and illustrated. To date, clinical reports of these treatments for prostate and head and neck cancers have the most mature data. Those results are summarized here. Future applications of this technology can be expected to take careful, considered advantage of this technology to further rearrange dose distributions across target volumes to produce an integrated overall gain in treatment objectives. However, these innovative applications need to be approached with caution, preferably in prospective clinical trials that would help determine if the hypothetical clinical benefits are in fact realizable. Semin Radiat Oncol 16:224-231 © 2006 Elsevier Inc. All rights reserved. KEYWORDS IMRT, radiotherapy treatment planning optimization
I
ntensity-modulated radiation therapy (IMRT), when planned by using an optimization engine, allows for great versatility in being able to distribute and rearrange the dose distribution in comparison to what can be easily accomplished in 3-dimensional conformal therapy. Beamlet IMRT, especially when incorporating many treatment fields, is capable of preferentially locating regions with high-dose gradients and in producing concave isodose surfaces. However, in terms of clinical application, the number of theoretical IMRT treatment planning studies and review articles looking into the future vastly outweighs the reporting of firm clinical data in the present. This is unfortunate because IMRT is currently both labor intensive and expensive. For target volumes well isolated from dose-limiting organs at risk for radiation injury, little optimization or dose modulation is needed. In this setting, IMRT is not required to produce a suitable patient treatment. It could be argued that having all of a particular treatment site’s clinical goals and objectives fully specified in terms of dose/volume and inte-
Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI Supported in part by NIH Grant P01CA59872. Address reprint requests to Randall K. Ten Haken, PhD, University of Michigan, Department of Radiation Oncology, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0010. E-mail: [email protected]
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1053-4296/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2006.04.005
grated dose effect metrics (eg, as they would need to be for use in an IMRT optimization cost function) should be part of good clinical practice, but this is not a sole justification for using IMRT. Optimized IMRT has its greatest clinical impact for treatments that may require great conformality or the need for a sharp-dose gradient in some particular region. However, these situations also force the clinical user to become more actively involved in the planning process because these difficult treatment scenarios most often require a compromise among planning objectives (ie, in these circumstances, an optimization engine is a sophisticated tool to aid the planner in what is still most often an iterative forward planning adventure). Clinical results would be most helpful in aiding the planner in these applications. This review begins with a discussion of the tradeoffs associated with target dose heterogeneity both as a consequence of IMRT planning and delivery, and presents areas where the clinical user needs to be more involved to fully exploit the clinical potentials of optimized IMRT. We then review some clinical results. We do not attempt to summarize the multiple papers in this area that report the results of small numbers of patients with short follow-up, but instead focus on two sites where we feel we have sufficient evidence to make some definitive statements: prostate cancer and head and neck can-
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Figure 1 (A) Nonaxial IMRT fields used to plan treatment of a brain tumor (light blue volume). Also shown are the optical pathway structures (eyes [light brown], optic nerves [red]; chiasm [yellow]), brainstem ([light gray]) and theoretical aggressive disease volume (red). PTV and selected normal tissue DVHs for (B) homogeneous PTV dose, (C) heterogeneous PTV dose and (D) heterogeneous PTV dose preferentially localized to aggressive disease region.
cer. We conclude with some thoughts about future applications of IMRT.
IMRT Planning and Delivery As recently summarized by Mackie and his colleagues,1 conformal therapy approaches apply best to situations with welldelineated targets, whereas conformal avoidance strategies are best applied in situations in which the dose needs to be severely limited (eg, with a sharp dose gradient) near a sensitive structure (where there is little likelihood of tumor extension). They point out that successful application of both of these strategies has become a practical reality only with the advent of nonuniform treatment fields (ie, IMRT). Starting with several early reports on the use of IMRT for conformal treatments,2-7 improvements in some treatment evaluation metric with the use of IMRT have been reported. Similarly, a recent report8 on IMRT for conformal avoidance in the pelvis indicates good coverage of pelvis and inguinal/femoral nodes while at the same time significantly sparing the surrounding organs at risk (OARs). Except for the few well-defined instances with good separation of all target volumes from critical normal tissue volumes, nearly every study in the comparative benefit of IMRT over 3-dimensional conformal planning has had to struggle with how to fairly report the perceived benefits of the resulting plans; that is, the clinical tradeoffs in IMRT planning are no different than they have always been (target dose coverage and homogeneity) and normal tissue doses (dose conformality to the region near the targets or away from certain normal tissues). IMRT together with a search engine allows the clinical user to choose from among many options the ones that most appropriately apply to the patient under consideration. This can, by definition, make comparisons among competing plans difficult and has led at times to a lack of satisfaction when attempting to evaluate the (sometimes very different looking) plans resulting from IMRT optimization. The ques-
tions generally relate to definitions of conformality and of dose heterogeneity across the target volumes. Pirzkall and coworkers7 have summarized the situation quite nicely in terms of competing target volume goals. They point out that complex treatment geometries (as might be appreciated for conformal or conformal avoidance IMRT) preclude the simultaneous achievement of all 3 of the common goals of modern planning (target-dose homogeneity, high-dose coverage, and dose conformality [structure sparing]). They contend that many 3-dimensional plans concentrated on maintaining target-dose homogeneity in a conformal manner, which (for target and critical normal tissues in close proximity) often limited target coverage (ie, prescription dose, the nearby normal tissue dictating the maximum dose that can be delivered homogeneously to the target). They go on to point out that other conformal techniques such as brachytherapy or stereotactic radiotherapy strive for high target dose and conformality (normal tissue avoidance) with minimized emphasis on target-dose homogeneity. Because of the challenging geometries, the clinical use of IMRT has often been associated with this later category (ie, the increase in conformality with IMRT has allowed higher prescription doses but often with increased target volume-dose heterogeneity). With the availability and integration of patient-specific information from (for example) functional imaging studies has also come the possibility to have the IMRT optimization system advantageously and preferentially rearrange the heterogeneous target-dose distribution to areas in which it may have the greatest impact.9,10 These points may be shown with an example. Figure 1A shows a noncoplanar arrangement of IMRT fields used to treat a brain tumor. The planning target volume (PTV) (outer light blue volume) includes the clinical target volume (CTV) with a small margin and is seen to infringe on the brainstem (and lies in the vicinity of the optical pathway structures, especially the chiasm). The inner (red) volume is illustrative of what may be a highly aggressive part of the tumor as
226 indicated on some supplementary imaging study that has been registered with the planning data. An initial IMRT plan performed by using traditional rules regarding conformality and target-dose homogeneity (and without special consideration of the additional imaging data) resulted in dose volume histograms (DVHs) reminiscent of those obtainable using conformal 3-dimensional planning (Fig 1B). Homogeneous dose escalation to the PTV is limited in this case by the doses to the adjacent normal structures. A second optimization was done with relaxed target volume homogeneity (but again without use of the functional imaging data) resulting in (Fig 1C) similar PTV minimum dose coverage (and normal tissue sparing) but also with regions of higher dose in the PTV. The equivalent uniform dose (EUD) for the target volume increased from ⬃62 Gy to ⬎71 Gy simply by relaxing homogeneity criteria for the PTV. As an additional exercise, we tried to rearrange the dose within the PTV to preferentially treat that part of the PTV indicated as being aggressive on the supplementary imaging study to high dose while maintaining adequate dose (ie, as in plan 1) to the rest of the PTV (assumed to be less aggressive and/or subclinical) and the doselimiting normal tissues. These goals were realized (Fig 1D) with an EUD for the aggressive part of the target volume in excess of 100 Gy. Although the principles have been shown previously, the heterogeneous target-volume dose distribution we see after IMRT optimization should still bring up a few questions related to its clinical utility. We might ask whether the PTV dose heterogeneity is always necessary with IMRT. We might ask about how to judge the potential effects of cold versus hot spots within the PTV. And, we might ask if there are situations in which we could take advantage of heterogeneous target-volume coverage with some potential patient benefit. We briefly address each of these questions in turn. Optimized IMRT plans are (of course) quite capable of achieving target-volume dose homogeneity at a comparable (or even at an increased) level compared with 3-dimensional conformal radiation therapy (CRT) (Fig 1B). One simply needs to specify the optimization problem with homogeneity as a priority (a priority, it should be mentioned that [as in the 3-dimensional case]) may only be achievable at a cost (eg, lower prescription dose). However, although conformality (and higher prescription doses) may be of clinical interest and used to advantage in some cases such as the treatment of central nervous system lesions,7,11 maintaining dose homogeneity may well be of higher interest for other treatment sites such as for head and neck lesions. For example, head and neck target volumes commonly encompass mucosa and submucosal tissue, nerves, and bone, all of which may undergo severe acute reactions or late complications if significant overdosage is delivered to a substantial (unknown, in most cases) volume.12 Because treatment of these cases can also lead to good clinical results at modest prescription doses,13 dose homogeneity may be a priority. Indeed, several studies have shown that such homogeneous target-dose objectives are possible for head and neck treatments while at the same time avoiding high dose to structures such as the major sali-
R.K. Ten Haken and T.S. Lawrence vary glands.12,14,15 Somewhat similar homogeneous dose considerations might apply for IMRT in the breast.16,17 Assessment of the potential impact of substantial dose heterogeneity across the target volume requires consideration of the prescription dose (ie, the dose relative to which there is heterogeneity) as well as the degree and direction of dose variance from that value. That is, if (as described earlier) hot spots may be potentially harmful, they need to be avoided, and (as mentioned) this is generally not difficult to control for clinical IMRT treatments. However, a more common source of concern has been related to assessing the impact of sections of the target volume planned to receive dose levels less than the prescription dose. These usually occur in regions of the PTV close to dose-limiting normal structures. Simple line of reasoning related to these cold spots might go along the lines of, if the improved conformality indicated by using optimized IMRT would allow an X% increase in prescription dose, then even if some small areas of the PTV were planned to be underdosed by that same X%, an overall benefit to the patient could be anticipated (or at worst, no loss of tumor control from the non-IMRT situation). Of course, things become much more complicated when trying to consider the ability for areas of higher dose within the target volume to make up for small dose cold spots, at any given prescription dose. Such considerations require the use of some sort of tumor control modeling, such as that discussed by Tome and Fowler.18 They computed that a dose deficit of 20% to even 1% volume of the target would lead to serious loss of tumor control, even if 80% of the target volume received a 10% dose boost. Thus, particular attention has to be paid to cold-dose regions in the target not accompanied by a permitted increase in prescription dose. These same biological model considerations are now becoming available for use in the optimization procedure. For example, the value of the generalized EUD of the target volume (dose that if given uniformly is modeled to have an equivalent biological effect to that of the heterogeneous dose distribution under consideration19) will always be somewhere between the minimum target dose and the mean target dose depending on the responsiveness of the tumor to irradiation. Thus, the deleterious effects of cold regions can be minimized if the EUD for the target is optimized to be equal to or larger than the prescription dose. Recently, some investigators have begun to look at targetvolume dose heterogeneity in a more positive manner; that is, as stated earlier (eg, Fig 1C and 1D), under controlled conditions, dose heterogeneity in the PTV can be exploited by using optimized IMRT to accomplish superior dose conformality (such that the minimum dose to the PTV can be maintained at as high a level as possible (as constrained by the most limiting nearby OAR) and the ability to substantially increase both the physical prescription dose and more significantly the overall integrated impact of the PTV dose distribution (as evaluated, for example, by using EUD). The most prevalent use of these techniques has been via the incorporation of simultaneous boosts within target volumes, either because of varying tumor loads9,20-22 or as a beneficial theoretical construct23,24 for target volumes already limited in
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Figure 2 (A) Color wash of isodose distribution for homogeneous conformal IMRT of the prostate for a low-risk patient. (B) IMRT optimized to produce proximal urethral sparing in the same patient.
minimum dose because of PTV and OAR overlap.25-27 These same dose heterogeneity playoffs can be observed in general conformal avoidance applications of IMRT8 or for inclusion of patient-specific OAR dose choices in the optimization process.28 One illustration of these latter considerations is presented in Figure 2. In Figure 2, the dose distribution across the prostate target volume has been rearranged for this lowrisk patient to decrease the dose to the proximal urethra without compromising overall integrated PTV coverage or increasing the dose to other normal structures in the pelvis.29 In addition to these issues related to target volume dose conformality and heterogeneity in the planning process, there should be a greater concern about actually achieving these plans in the face of patient setup uncertainty and organ motion. Actual realization of the highly conformal clinical applications most appropriate for use of IMRT requires precise localization of both target and normal tissue structures at both the planning and treatment stages. Furthermore, the ability to guarantee and/or continuously verify these assumptions significantly challenges the routine clinical (justification and) use of IMRT.1 Simply expanding PTVs to include these geometric effects defeats the primary gains that may be achieved by using optimized IMRT. Likewise, by using the same conformality, prescription dose, and target dose heterogeneity concerns as described previously, even a very conformal dose delivery to a PTV that includes a large margin around the CTV will generally be limited in prescription dose by concerns related to organs at risk, that will by definition
227 now be even closer to (abutting if not in fact overlapping) the PTV. It is unlikely that even a very heterogeneous targetvolume dose distribution will be able to make up for the lower prescription dose and/or cold-dose region necessary to accommodate the large PTV expansion. Conversely, to ignore the uncertainties and use an overly small PTV expansion is also clinically unjustified. One might just as well safely apply 3-dimensional CRT techniques to the PTV, albeit to lower than desired target doses. Although organ motion and setup uncertainty are only minimal issues at some treatment sites (eg, stereotactic radiotherapy in the brain), without strict immobilization and localization techniques, they can still lead to unwanted consequences for treatments at other clinical sites, even for treatments of head and neck tumors as clearly shown in recent reports by Hong and coworkers30 and Ploquin and coworkers.31 Both of these studies point out the need to carefully monitor patients over the whole course of treatment and that more rigorous immobilization techniques than conventional masking and routine patient setup tracking methodologies are important for the accurate monitoring and successful delivery of high-quality IMRT for head and neck cancer. Similar conclusions can be reached for IMRT treatments at other sites in which small PTV margins are often used, such as in the prostate.32 Of course, the issues become even more complicated for treatments in the abdomen33 or thorax34 in which motion reduction can also be an issue.35 As indicated by Bortfeld and coworkers36 in their recent review of these concerns, if there is in fact a tendency in IMRT treatment planning to reduce or compromise target margins, the dose blurring caused by treatment delivery uncertainties has potentially an even bigger effect on the outcome of IMRT than it would on conformal therapy, unless precise dose-delivery techniques are also used.
Dose Optimization in Clinical Practice Before describing the results of treatment with IMRT, it is important to consider the type of evidence needed to draw conclusions. Radiation therapy differs from drug therapy in a fundamental manner. In the case of drug therapy, it has not been possible to develop a model system based on first principles to determine whether one drug is superior to another. We have numerous examples of drugs that worked well in animal models, for instance, that are discovered to have serious and unexpected toxicities in human beings. Thus, the acceptance of a new drug can only be established through a randomized trial. In contrast to drug therapy, radiation therapy follows physical principles. For the same tumor coverage, if technology A treats less normal tissue than technology B, technology A is superior. Likewise, for the same normal-tissue coverage, if technology A can deliver a higher dose to the tumor than technology B, then technology A is superior. Many important issues are, of course, hidden in this simple formulation. By “technology A,” one does not simply mean a computer exer-
228 cise. One must mean the technology as planned and delivered to a patient, with all of the clinical and geometric uncertainties associated with treatment that were described earlier. Thus, the characterization of the technology must be based on the actual doses delivered, not simply the theoretical doses based on laboratory simulations (usually performed on a single static CT image). Note, this discussion is not specific to IMRT because our field attempted to address this same issue in the comparison of 2-dimensional therapy to 3-dimensional conformal therapy. We do not feel it will be possible to run head-to-head randomized trials of IMRT versus 3-dimensional conformal therapy in the United States. Such a trial would be strictly about cost. On the other hand, IMRT permits one to ask questions about dose and dose distributions that were previously not testable. Most simply, we can ask whether even higher doses, now tolerable because more normal tissue can be spared, can increase tumor control, compared with standard doses, but all delivered with the same state of the art technology. We have precedence for this form of development using 3-dimensional conformal therapy. The technological advance from 2-dimensional to 3-dimensional permitted us to ask the dose question, and there are now two randomized trials37,38 showing that higher doses of photon radiation increase biochemical no evidence of disease (bNED) survival compared with lower doses in the treatment of prostate cancer. The development of IMRT also enables us to test a new type of hypothesis concerning dose localization. For instance, for the same toxicity, is it better to give a homogenous target dose or higher doses to regions of the target predicted to be resistant at the expense of lower doses to regions not predicted to be resistant? However, we must also face the possibility that if such trials show no clinical improvement from the doses or dose localizations permitted by the new technology, then the new approach may not be useful in that setting. In other words, although head-to-head trials of IMRT versus 3-dimensional are probably not feasible, we may conclude that in certain clinical settings the benefits provided by IMRT are not measurable and that 3-dimensional therapy would be sufficient. We see the development pathway for new technologies to begin with the validation of the principle by realistic “drylaboratory” calculation (including estimates of geometric uncertainties and organ motion) and initial phase I and phase II trials to set the parameters for the dose questions (either higher tumor dose or lower normal-tissue dose) that will subsequently be answered in a randomized trial. Therefore, we would strongly encourage the use of IMRT on prospective trials until the randomized dose trials can be constructed. This strategy has, unfortunately, not been adopted in the United States, and there appears to be widespread use of IMRT off study in situations in which the clinical benefit is far from proven but the cost of treatment has been increased.
Prostate Cancer Prostate cancer would seem to be an attractive site for the consideration of IMRT. There is strong evidence that increas-
R.K. Ten Haken and T.S. Lawrence ing dose increases bNED survival,37-39 yet dose escalation is difficult because of rectal and bladder toxicity. Because the prostate and seminal vesicles represent a concave target with respect to the dose-limiting OAR of the rectum, IMRT would be anticipated to permit dose escalation with improved outcome. Given the strong rationale, it is disappointing that there are so few systematic reports on the late toxicity of IMRT compared with 3-dimensional conformal therapy in the treatment of prostate cancer. Although a number of studies have evaluated acute effects (eg, Teh and coworkers40), the only large reported series with reasonable follow-up is that of Zelefsky and colleagues,41 which will therefore be examined in some detail. They described the results of treatment of 772 patients with a spectrum of clinically localized prostate cancers, 90% of whom received 81 Gy and the remainder 86.4 Gy. This was a minimum PTV dose, except for the region in which the PTV overlapped with the rectum; dose to this region was limited to 88% of the prescription dose (71 and 76 Gy, respectively). Only the initial 11% of the patients was treated on a prospective trial. The overall result of this study was that only about 0.5% of patients had late grade 3 genitourinary (GU) or gastrointestinal (GI) toxicity. Although the follow-up period was short, there was no suggestion that bNED survival was compromised by the application of this new technology. These results appear to be modestly superior to the recent study by the Radiation Therapy Oncology Group (RTOG) of the results of treatment at “level 5” of a prostate dose escalation trial (RTOG 9406). At level 5, the minimum target dose was 77.9 Gy, and the median target dose was 81.4 Gy. In this study, about 3.7% and 3.2% of the patients evidenced late grade 3 GU or GI toxicity.42 Therefore, although modern 3-dimensional conformal therapy can deliver doses in the range of 78 to 80 Gy with moderate acute but low long-term toxicity, IMRT, at least as delivered at the Memorial Sloan Kettering Cancer Center, New York, NY, appears to offer a modest decrease in toxicity.
Head and Neck Cancer In the case of head and neck cancer, the goal of treatment with IMRT for most clinical trials has been to reduce normal tissue toxicity while preserving tumor control.43-45 Before investigators undertook detailed studies of improved dose conformality to decrease toxicity, the focus of head and neck research was on fractionation and the role of combined radiation and chemotherapy. Although hyperfractionated and accelerated radiation approaches have been shown to be superior to once daily radiation alone,46 it is not yet clear whether this difference is maintained in patients receiving chemotherapy. Thus, there are at least two “standard” approaches using combined chemotherapy and radiation for the treatment of patients with unresectable disease: one using twice daily radiation and another using once daily radiation (for meta-analysis, see Pignon and coworkers47). It is not the purpose of this review to focus on this question, but, given the time and labor involved in IMRT delivery and the absence
Intensity-modulated radiation therapy of data that twice-daily radiation with chemotherapy is superior, current IMRT approaches have tended to focus on oncedaily radiation with chemotherapy. For patients with unresectable head and neck cancers treated once daily (with chemotherapy), the gross tumor typically receives a dose of 70 Gy in 2 Gy fractions, areas at risk for subclinical disease may receive 46 to 50 Gy, and regions at high risk for subclinical disease receive 60 to 64 Gy. These doses would be achieved by using successive boosts, and thus all treatment would be in 2-Gy fractions. Two main clinical strategies have been used to implement and, hopefully, improve on this general approach. Each tries to produce the greatest possible difference between the dose to the tumor and the adjacent parotid glands and spinal cord. The first involves keeping the gross tumor dose at 2 Gy per fraction. This requires treating the regions at risk for subclinical disease at lower doses per fraction and estimating a biocorrection for fraction size. This approach would be expected to produce the same tumor control as conventional chemoradiation approaches, with the “pure” goal of decreased toxicity. The risk in this strategy is that subclinical disease might receive insufficient dose, depending on the accuracy of biocorrection for the lower dose per fraction. A second approach has proposed using greater than 2 Gy per fraction (in the range of 2.2-2.4 Gy) to the tumor. Here the goal is to use IMRT to accelerate treatment without substantially increasing toxicity. The risk to this approach is that it could be substantially more toxic than standard therapy, depending on how well improved dose distributions of IMRT can translate into decreased toxicity when combined with chemotherapy. Both approaches share a risk of marginal misses that can occur when more conformal delivery is attempted. With respect to the first strategy described previously, there are now clinical studies from a number of institutions that suggest that IMRT can be used to spare parotid function while maintaining local-regional control rates. Although we are not aware of any completed randomized trials between IMRT and non-IMRT therapies, preliminary results from an ongoing study48 suggest that patients treated by using IMRT had less xerostomia than those treated by using 2-dimensional radiation therapy at 6 weeks (P ⬍ .002) and 6 months (P ⬍ .06) after treatment. A growing number of single-institution studies49-51 all have sufficient numbers of patients (⬎50) and median follow-up (⬎3 years) showing local failure rates in the range of 10% to 15%, few marginal failures, and preservation of parotid function. It would be anticipated that detailed studies of these marginal failures will improve target definition and improve on these results. Although these clinical findings are very encouraging, there are several caveats to this conclusion. First, modest but potentially significant clinical differences in control rates between more standard approaches and IMRT cannot yet be definitively assessed because of the heterogeneity of sites, stages, and other treatments found in all head and neck series. Second, attempts to take advantage of the greater conformality of IMRT requires a detailed understanding of head and neck anatomy that was not a routine part of clinical training for most radiation oncologists graduating more than
229 3 years ago. New training will be required for most radiation oncologists who wish to apply this technology appropriately. Third, the relationship between parotid salivary flow and the subjective sense of xerostomia may be weaker than was originally anticipated, and organs such as the minor salivary glands (which are not always spared with IMRT) may play an important role in the patient’s quality of life. Fourth, other toxicities that have not yet been addressed may affect quality of life to an equal or greater extent than xerostomia, although initial clinical efforts suggest that IMRT may be able to decrease this toxicity as well.45 Thus, the overall benefit of IMRT based on OARs of the spinal cord and parotids is still not fully defined. Much less is known about the second strategy of using IMRT for dose escalation. The most recent publications concerning the clinical outcomes20,22 suggest that escalation to 2.3 to 2.4 Gy fractions may be possible with radiation alone, but whether this is tolerable with concurrent chemotherapy is not determined. Likewise, there are insufficient data to assess the effect of this approach on local regional tumor control. It would seem that this approach should be limited to prospective clinical trials.
Other Sites A number of sites in addition to head and neck and prostate cancer have been explored, although few long-term clinical results are available. With regard to breast cancer, a randomized trial has been conducted comparing 2-dimensional radiotherapy with 3-dimensional intensity-modulated treated using static fields. The preliminary results of this study have been published in abstract form52 and will soon be submitted for publication (J Yarnold, personal communication, January, 2006). The results show a clinically and statistically significant reduction in the probability of change in breast appearance and palpable induration in the group allocated 3-dimensional dosimetry delivered via multiple static fields. No long-term results of treatment are available for patients receiving IMRT for gynecologic cancers, but some evidence suggests that acute toxicity may be decreased.53 Clinical data from patients receiving treatment for gliomas and lung cancer are too preliminary to permit analysis.
Conclusions IMRT with optimization in planning can be viewed as a technology that enables us to better achieve the goals of treatment planning that we have always had including (1) maximizing target dose, (2) improving target homogeneity, and (3) avoiding organs at risk (although, as pointed out earlier, it may not be able to do all 3 at once). The opportunities to avoid critical normal tissues and to arrange dose within the target to achieve specified ends is greatly enhanced over what can be achieved even with very good 3-dimensional planning. However, these goals can only be accomplished by paying meticulous attention to technical aspects of planning, localization, and delivery. In the case of prostate cancer and head and neck cancer, current evidence does suggest that IMRT permits us
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230 to safely increase dose (in the former) and to protect the parotid glands (in the latter). Although the clinical data on intracranial tumors is limited, the ability to image tumors and critical normal structures, combined with the excellent immobilization that can typically be achieved, suggest this should be a fruitful site for study. Other tumor types, such as lung, breast, and gynecologic cancers, present issues of target definition, localization, and organ motion that would seem to require additional investigation before IMRT becomes standard. Unfortunately, only a small fraction of patients receiving IMRT are currently treated on prospective trials, which is the only way to begin to determine if the hypothetical clinical benefits are actually realized. Given the greater expense of IMRT, it will be critical to better quantify its benefit in future studies.
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comparative analysis of dosimetric and technical parameters. Int J Radiat Oncol Biol Phys 58:617-624, 2004 Kestin LL, Sharpe MB, Frazier RC, et al: Intensity modulation to improve dose uniformity with tangential breast radiotherapy: Initial clinical experience. Int J Radiat Oncol Biol Phys 48:1559-1568, 2000 Krueger EA, Fraass BA, Pierce LJ: Clinical aspects of intensity-modulated radiotherapy in the treatment of breast cancer. Semin Radiat Oncol 12:250-259, 2002 Tome WA, Fowler JF: On cold spots in tumor subvolumes. Med Phys 29:1590-1598, 2002 Niemierko A: A generalized concept of equivalent uniform dose (EUD). Med Phys 26:1100, 1999 (abstr) Butler EB, Teh BS, Grant WH 3rd, et al: Smart (simultaneous modulated accelerated radiation therapy) boost: A new accelerated fractionation schedule for the treatment of head and neck cancer with intensity modulated radiotherapy. Int J Radiat Oncol Biol Phys 45:21-32, 1999 Mohan R, Wu Q, Manning M, et al: Radiobiological considerations in the design of fractionation strategies for intensity-modulated radiation therapy of head and neck cancers. Int J Radiat Oncol Biol Phys 46:619630, 2000 Lauve A, Morris M, Schmidt-Ullrich R, et al: Simultaneous integrated boost intensity-modulated radiotherapy for locally advanced headand-neck squamous cell carcinomas: II—Clinical results. Int J Radiat Oncol Biol Phys 60:374-387, 2004 Tome WA, Fowler JF: Selective boosting of tumor subvolumes. Int J Radiat Oncol Biol Phys 48:593-599, 2000 Deasy JO: Partial tumor boosts: Even more attractive than theory predicts?. Int J Radiat Oncol Biol Phys 51:279-280, 2001 Schwarz M, Alber M, Lebesque JV, et al: Dose heterogeneity in the target volume and intensity-modulated radiotherapy to escalate the dose in the treatment of non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 62:561-570, 2005 Thomas E, Chapet O, Kessler ML, et al: Benefit of using biologic parameters (EUD and NTCP) in IMRT optimization for treatment of intrahepatic tumors. Int J Radiat Oncol Biol Phys 62:571-578, 2005 Chapet O, Thomas E, Kessler ML, et al: Esophagus sparing with IMRT in lung tumor irradiation: An EUD-based optimization technique. Int J Radiat Oncol Biol Phys 63:179-187, 2005 Tsien C, Eisbruch A, McShan D, et al: Intensity-modulated radiation therapy (IMRT) for locally advanced paranasal sinus tumors: incorporating clinical decisions in the optimization process. Int J Radiat Oncol Biol Phys 55:776-784, 2003 Lopez CA, Pan CC, Sandler HM, et al: Early results of a prospective randomized trial comparing proximal urethra sparing IMRT and standard prostate IMRT in low-risk prostate cancer patients. Program Guide to the 2005 Scientific Assembly of the RSNA, Chicago, IL, November 2005, p 455 (abstr) Hong TS, Tome WA, Chappell RJ, et al: The impact of daily setup variations on head-and-neck intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 61:779-788, 2005 Ploquin N, Song W, Lau H, et al: Intensity modulated radiation therapy for oropharyngeal cancer: The sensitivity of plan objectives and constraints to set-up uncertainty. Phys Med Biol 50:3515-3533, 2005 Litzenberg DW, Balter JM, Lam KL, et al: Retrospective analysis of prostate cancer patients with implanted gold markers using off-line and adaptive therapy protocols. Int J Radiat Oncol Biol Phys 63:123-133, 2005 Balter JM, Brock KK, Lam KL, et al: Evaluating the influence of setup uncertainties on treatment planning for focal liver tumors. Int J Radiat Oncol Biol Phys 63:610-614, 2005 Seppenwoolde Y, Shirato H, Kitamura K, et al: Precise and real-time measurement of 3D tumor motion in lung due to breathing and heartbeat, measured during radiotherapy. Int J Radiat Oncol Biol Phys 53: 822-834, 2002 Dawson LA, Balter JM: Interventions to reduce organ motion effects in radiation delivery. Semin Radiat Oncol 14:76-80, 2004 Bortfeld T, Jiang SB, Rietzel E: Effects of motion on the total dose distribution. Semin Radiat Oncol 14:41-51, 2004 Pollack A, Zagars GK, Starkschall G, et al: Prostate cancer radiation
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dose response: Results of the M. D. Anderson phase III randomized trial Int J Radiat Oncol Biol Phys 53:1097-1105, 2002 Lebesque JV, Peeters STH, van Putten WLJ, et al: Radiation dose-response in prostate cancer: Results of a multicenter randomized phase III trial comparing 68Gy with 78Gy. Eur J Cancer Suppl 3:1, 2005 (abstr) Symon Z, Griffith KA, McLaughlin PW, et al: Dose escalation for localized prostate cancer: Substantial benefit observed with 3D conformal therapy. Int J Radiat Oncol Biol Phys 57:384-390, 2003 Teh BS, Amosson CM, Mai WY, et al: Intensity modulated radiation therapy (IMRT) in the management of prostate cancer. Cancer Invest 22:913-924, 2004 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 53:1111-1116, 2002 Michalski JM, Winter K, Purdy JA, et al: Toxicity after three-dimensional radiotherapy for prostate cancer with RTOG 9406 dose level IV. Int J Radiat Oncol Biol Phys 58:735-742, 2004 Hong TS, Ritter MA, Tome WA, et al: Intensity-modulated radiation therapy: Emerging cancer treatment technology. Br J Cancer 92:18191824, 2005 Gregoire V, Maingon P: Intensity modulated radiation therapy in head and neck squamous cell carcinoma: State of the art and future challenges. Cancer Radiother 9:42-50, 2005 Eisbruch A: Intensity-modulated radiation therapy in the treatment of head and neck cancer. Nat Clin Pract Oncol 2:34-39, 2005 Fu KK, Pajak TF, Trotti A, et al: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation
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and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: First report of RTOG 9003. Int J Radiat Oncol Biol Phys 48:7-16, 2000 Pignon JP, Bourhis J, Domenge C, et al: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-analysis of chemotherapy on head and neck cancer. Lancet 355:949-955, 2000 Kam MK, Leung SF, Zee B, et al: Impact of intensity-modulated radiotherapy (IMRT) on salivary gland function in early-stage nasopharyngeal carcinoma (NPC) patients: A prospective randomized study. J Clin Oncol, 2005 ASCO Annual Meeting Proceedings 23:5501, 2005 (abstr) Dawson LA, Anzai Y, Marsh L, et al: Patterns of local-regional recurrence following parotid-sparing conformal and segmental intensitymodulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 46:1117-1126, 2000 Lee N, Xia P, Quivey JM, et al: Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: An update of the UCSF experience. Int J Radiat Oncol Biol Phys 53:12-22, 2002 Chao KS, Low DA, Perez CA, et al: Intensity-modulated radiation therapy in head and neck cancers: The Mallinckrodt experience. Int J Cancer 90:92-103, 2000 Yarnold J, Donovan E, Bleackley N, et al: Randomised trial of standard 2D radiotherapy (RT) versus 3D intensity modulated radiotherapy (IMRT) in patients prescribed breast radiotherapy. Clin Oncol 14:S40, 2002 (abstr) Mundt AJ, Mell LK, Roeske JC: Preliminary analysis of chronic gastrointestinal toxicity in gynecology patients treated with intensity-modulated whole pelvic radiation therapy. Int J Radiat Oncol Biol Phys 56: 1354-1360, 2003
I
ntensity-modulated radiation therapy (IMRT), when planned by using an optimization engine, allows for great versatility in being able to distribute and rearrange the dose distribution in comparison to what can be easily accomplished in 3-dimensional conformal therapy. Beamlet IMRT, especially when incorporating many treatment fields, is capable of preferentially locating regions with high-dose gradients and in producing concave isodose surfaces. However, in terms of clinical application, the number of theoretical IMRT treatment planning studies and review articles looking into the future vastly outweighs the reporting of firm clinical data in the present. This is unfortunate because IMRT is currently both labor intensive and expensive. For target volumes well isolated from dose-limiting organs at risk for radiation injury, little optimization or dose modulation is needed. In this setting, IMRT is not required to produce a suitable patient treatment. It could be argued that having all of a particular treatment site’s clinical goals and objectives fully specified in terms of dose/volume and inte-
Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI Supported in part by NIH Grant P01CA59872. Address reprint requests to Randall K. Ten Haken, PhD, University of Michigan, Department of Radiation Oncology, 1500 E. Medical Center Drive, Ann Arbor, MI 48109-0010. E-mail: [email protected]
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1053-4296/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2006.04.005
grated dose effect metrics (eg, as they would need to be for use in an IMRT optimization cost function) should be part of good clinical practice, but this is not a sole justification for using IMRT. Optimized IMRT has its greatest clinical impact for treatments that may require great conformality or the need for a sharp-dose gradient in some particular region. However, these situations also force the clinical user to become more actively involved in the planning process because these difficult treatment scenarios most often require a compromise among planning objectives (ie, in these circumstances, an optimization engine is a sophisticated tool to aid the planner in what is still most often an iterative forward planning adventure). Clinical results would be most helpful in aiding the planner in these applications. This review begins with a discussion of the tradeoffs associated with target dose heterogeneity both as a consequence of IMRT planning and delivery, and presents areas where the clinical user needs to be more involved to fully exploit the clinical potentials of optimized IMRT. We then review some clinical results. We do not attempt to summarize the multiple papers in this area that report the results of small numbers of patients with short follow-up, but instead focus on two sites where we feel we have sufficient evidence to make some definitive statements: prostate cancer and head and neck can-
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Figure 1 (A) Nonaxial IMRT fields used to plan treatment of a brain tumor (light blue volume). Also shown are the optical pathway structures (eyes [light brown], optic nerves [red]; chiasm [yellow]), brainstem ([light gray]) and theoretical aggressive disease volume (red). PTV and selected normal tissue DVHs for (B) homogeneous PTV dose, (C) heterogeneous PTV dose and (D) heterogeneous PTV dose preferentially localized to aggressive disease region.
cer. We conclude with some thoughts about future applications of IMRT.
IMRT Planning and Delivery As recently summarized by Mackie and his colleagues,1 conformal therapy approaches apply best to situations with welldelineated targets, whereas conformal avoidance strategies are best applied in situations in which the dose needs to be severely limited (eg, with a sharp dose gradient) near a sensitive structure (where there is little likelihood of tumor extension). They point out that successful application of both of these strategies has become a practical reality only with the advent of nonuniform treatment fields (ie, IMRT). Starting with several early reports on the use of IMRT for conformal treatments,2-7 improvements in some treatment evaluation metric with the use of IMRT have been reported. Similarly, a recent report8 on IMRT for conformal avoidance in the pelvis indicates good coverage of pelvis and inguinal/femoral nodes while at the same time significantly sparing the surrounding organs at risk (OARs). Except for the few well-defined instances with good separation of all target volumes from critical normal tissue volumes, nearly every study in the comparative benefit of IMRT over 3-dimensional conformal planning has had to struggle with how to fairly report the perceived benefits of the resulting plans; that is, the clinical tradeoffs in IMRT planning are no different than they have always been (target dose coverage and homogeneity) and normal tissue doses (dose conformality to the region near the targets or away from certain normal tissues). IMRT together with a search engine allows the clinical user to choose from among many options the ones that most appropriately apply to the patient under consideration. This can, by definition, make comparisons among competing plans difficult and has led at times to a lack of satisfaction when attempting to evaluate the (sometimes very different looking) plans resulting from IMRT optimization. The ques-
tions generally relate to definitions of conformality and of dose heterogeneity across the target volumes. Pirzkall and coworkers7 have summarized the situation quite nicely in terms of competing target volume goals. They point out that complex treatment geometries (as might be appreciated for conformal or conformal avoidance IMRT) preclude the simultaneous achievement of all 3 of the common goals of modern planning (target-dose homogeneity, high-dose coverage, and dose conformality [structure sparing]). They contend that many 3-dimensional plans concentrated on maintaining target-dose homogeneity in a conformal manner, which (for target and critical normal tissues in close proximity) often limited target coverage (ie, prescription dose, the nearby normal tissue dictating the maximum dose that can be delivered homogeneously to the target). They go on to point out that other conformal techniques such as brachytherapy or stereotactic radiotherapy strive for high target dose and conformality (normal tissue avoidance) with minimized emphasis on target-dose homogeneity. Because of the challenging geometries, the clinical use of IMRT has often been associated with this later category (ie, the increase in conformality with IMRT has allowed higher prescription doses but often with increased target volume-dose heterogeneity). With the availability and integration of patient-specific information from (for example) functional imaging studies has also come the possibility to have the IMRT optimization system advantageously and preferentially rearrange the heterogeneous target-dose distribution to areas in which it may have the greatest impact.9,10 These points may be shown with an example. Figure 1A shows a noncoplanar arrangement of IMRT fields used to treat a brain tumor. The planning target volume (PTV) (outer light blue volume) includes the clinical target volume (CTV) with a small margin and is seen to infringe on the brainstem (and lies in the vicinity of the optical pathway structures, especially the chiasm). The inner (red) volume is illustrative of what may be a highly aggressive part of the tumor as
226 indicated on some supplementary imaging study that has been registered with the planning data. An initial IMRT plan performed by using traditional rules regarding conformality and target-dose homogeneity (and without special consideration of the additional imaging data) resulted in dose volume histograms (DVHs) reminiscent of those obtainable using conformal 3-dimensional planning (Fig 1B). Homogeneous dose escalation to the PTV is limited in this case by the doses to the adjacent normal structures. A second optimization was done with relaxed target volume homogeneity (but again without use of the functional imaging data) resulting in (Fig 1C) similar PTV minimum dose coverage (and normal tissue sparing) but also with regions of higher dose in the PTV. The equivalent uniform dose (EUD) for the target volume increased from ⬃62 Gy to ⬎71 Gy simply by relaxing homogeneity criteria for the PTV. As an additional exercise, we tried to rearrange the dose within the PTV to preferentially treat that part of the PTV indicated as being aggressive on the supplementary imaging study to high dose while maintaining adequate dose (ie, as in plan 1) to the rest of the PTV (assumed to be less aggressive and/or subclinical) and the doselimiting normal tissues. These goals were realized (Fig 1D) with an EUD for the aggressive part of the target volume in excess of 100 Gy. Although the principles have been shown previously, the heterogeneous target-volume dose distribution we see after IMRT optimization should still bring up a few questions related to its clinical utility. We might ask whether the PTV dose heterogeneity is always necessary with IMRT. We might ask about how to judge the potential effects of cold versus hot spots within the PTV. And, we might ask if there are situations in which we could take advantage of heterogeneous target-volume coverage with some potential patient benefit. We briefly address each of these questions in turn. Optimized IMRT plans are (of course) quite capable of achieving target-volume dose homogeneity at a comparable (or even at an increased) level compared with 3-dimensional conformal radiation therapy (CRT) (Fig 1B). One simply needs to specify the optimization problem with homogeneity as a priority (a priority, it should be mentioned that [as in the 3-dimensional case]) may only be achievable at a cost (eg, lower prescription dose). However, although conformality (and higher prescription doses) may be of clinical interest and used to advantage in some cases such as the treatment of central nervous system lesions,7,11 maintaining dose homogeneity may well be of higher interest for other treatment sites such as for head and neck lesions. For example, head and neck target volumes commonly encompass mucosa and submucosal tissue, nerves, and bone, all of which may undergo severe acute reactions or late complications if significant overdosage is delivered to a substantial (unknown, in most cases) volume.12 Because treatment of these cases can also lead to good clinical results at modest prescription doses,13 dose homogeneity may be a priority. Indeed, several studies have shown that such homogeneous target-dose objectives are possible for head and neck treatments while at the same time avoiding high dose to structures such as the major sali-
R.K. Ten Haken and T.S. Lawrence vary glands.12,14,15 Somewhat similar homogeneous dose considerations might apply for IMRT in the breast.16,17 Assessment of the potential impact of substantial dose heterogeneity across the target volume requires consideration of the prescription dose (ie, the dose relative to which there is heterogeneity) as well as the degree and direction of dose variance from that value. That is, if (as described earlier) hot spots may be potentially harmful, they need to be avoided, and (as mentioned) this is generally not difficult to control for clinical IMRT treatments. However, a more common source of concern has been related to assessing the impact of sections of the target volume planned to receive dose levels less than the prescription dose. These usually occur in regions of the PTV close to dose-limiting normal structures. Simple line of reasoning related to these cold spots might go along the lines of, if the improved conformality indicated by using optimized IMRT would allow an X% increase in prescription dose, then even if some small areas of the PTV were planned to be underdosed by that same X%, an overall benefit to the patient could be anticipated (or at worst, no loss of tumor control from the non-IMRT situation). Of course, things become much more complicated when trying to consider the ability for areas of higher dose within the target volume to make up for small dose cold spots, at any given prescription dose. Such considerations require the use of some sort of tumor control modeling, such as that discussed by Tome and Fowler.18 They computed that a dose deficit of 20% to even 1% volume of the target would lead to serious loss of tumor control, even if 80% of the target volume received a 10% dose boost. Thus, particular attention has to be paid to cold-dose regions in the target not accompanied by a permitted increase in prescription dose. These same biological model considerations are now becoming available for use in the optimization procedure. For example, the value of the generalized EUD of the target volume (dose that if given uniformly is modeled to have an equivalent biological effect to that of the heterogeneous dose distribution under consideration19) will always be somewhere between the minimum target dose and the mean target dose depending on the responsiveness of the tumor to irradiation. Thus, the deleterious effects of cold regions can be minimized if the EUD for the target is optimized to be equal to or larger than the prescription dose. Recently, some investigators have begun to look at targetvolume dose heterogeneity in a more positive manner; that is, as stated earlier (eg, Fig 1C and 1D), under controlled conditions, dose heterogeneity in the PTV can be exploited by using optimized IMRT to accomplish superior dose conformality (such that the minimum dose to the PTV can be maintained at as high a level as possible (as constrained by the most limiting nearby OAR) and the ability to substantially increase both the physical prescription dose and more significantly the overall integrated impact of the PTV dose distribution (as evaluated, for example, by using EUD). The most prevalent use of these techniques has been via the incorporation of simultaneous boosts within target volumes, either because of varying tumor loads9,20-22 or as a beneficial theoretical construct23,24 for target volumes already limited in
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Figure 2 (A) Color wash of isodose distribution for homogeneous conformal IMRT of the prostate for a low-risk patient. (B) IMRT optimized to produce proximal urethral sparing in the same patient.
minimum dose because of PTV and OAR overlap.25-27 These same dose heterogeneity playoffs can be observed in general conformal avoidance applications of IMRT8 or for inclusion of patient-specific OAR dose choices in the optimization process.28 One illustration of these latter considerations is presented in Figure 2. In Figure 2, the dose distribution across the prostate target volume has been rearranged for this lowrisk patient to decrease the dose to the proximal urethra without compromising overall integrated PTV coverage or increasing the dose to other normal structures in the pelvis.29 In addition to these issues related to target volume dose conformality and heterogeneity in the planning process, there should be a greater concern about actually achieving these plans in the face of patient setup uncertainty and organ motion. Actual realization of the highly conformal clinical applications most appropriate for use of IMRT requires precise localization of both target and normal tissue structures at both the planning and treatment stages. Furthermore, the ability to guarantee and/or continuously verify these assumptions significantly challenges the routine clinical (justification and) use of IMRT.1 Simply expanding PTVs to include these geometric effects defeats the primary gains that may be achieved by using optimized IMRT. Likewise, by using the same conformality, prescription dose, and target dose heterogeneity concerns as described previously, even a very conformal dose delivery to a PTV that includes a large margin around the CTV will generally be limited in prescription dose by concerns related to organs at risk, that will by definition
227 now be even closer to (abutting if not in fact overlapping) the PTV. It is unlikely that even a very heterogeneous targetvolume dose distribution will be able to make up for the lower prescription dose and/or cold-dose region necessary to accommodate the large PTV expansion. Conversely, to ignore the uncertainties and use an overly small PTV expansion is also clinically unjustified. One might just as well safely apply 3-dimensional CRT techniques to the PTV, albeit to lower than desired target doses. Although organ motion and setup uncertainty are only minimal issues at some treatment sites (eg, stereotactic radiotherapy in the brain), without strict immobilization and localization techniques, they can still lead to unwanted consequences for treatments at other clinical sites, even for treatments of head and neck tumors as clearly shown in recent reports by Hong and coworkers30 and Ploquin and coworkers.31 Both of these studies point out the need to carefully monitor patients over the whole course of treatment and that more rigorous immobilization techniques than conventional masking and routine patient setup tracking methodologies are important for the accurate monitoring and successful delivery of high-quality IMRT for head and neck cancer. Similar conclusions can be reached for IMRT treatments at other sites in which small PTV margins are often used, such as in the prostate.32 Of course, the issues become even more complicated for treatments in the abdomen33 or thorax34 in which motion reduction can also be an issue.35 As indicated by Bortfeld and coworkers36 in their recent review of these concerns, if there is in fact a tendency in IMRT treatment planning to reduce or compromise target margins, the dose blurring caused by treatment delivery uncertainties has potentially an even bigger effect on the outcome of IMRT than it would on conformal therapy, unless precise dose-delivery techniques are also used.
Dose Optimization in Clinical Practice Before describing the results of treatment with IMRT, it is important to consider the type of evidence needed to draw conclusions. Radiation therapy differs from drug therapy in a fundamental manner. In the case of drug therapy, it has not been possible to develop a model system based on first principles to determine whether one drug is superior to another. We have numerous examples of drugs that worked well in animal models, for instance, that are discovered to have serious and unexpected toxicities in human beings. Thus, the acceptance of a new drug can only be established through a randomized trial. In contrast to drug therapy, radiation therapy follows physical principles. For the same tumor coverage, if technology A treats less normal tissue than technology B, technology A is superior. Likewise, for the same normal-tissue coverage, if technology A can deliver a higher dose to the tumor than technology B, then technology A is superior. Many important issues are, of course, hidden in this simple formulation. By “technology A,” one does not simply mean a computer exer-
228 cise. One must mean the technology as planned and delivered to a patient, with all of the clinical and geometric uncertainties associated with treatment that were described earlier. Thus, the characterization of the technology must be based on the actual doses delivered, not simply the theoretical doses based on laboratory simulations (usually performed on a single static CT image). Note, this discussion is not specific to IMRT because our field attempted to address this same issue in the comparison of 2-dimensional therapy to 3-dimensional conformal therapy. We do not feel it will be possible to run head-to-head randomized trials of IMRT versus 3-dimensional conformal therapy in the United States. Such a trial would be strictly about cost. On the other hand, IMRT permits one to ask questions about dose and dose distributions that were previously not testable. Most simply, we can ask whether even higher doses, now tolerable because more normal tissue can be spared, can increase tumor control, compared with standard doses, but all delivered with the same state of the art technology. We have precedence for this form of development using 3-dimensional conformal therapy. The technological advance from 2-dimensional to 3-dimensional permitted us to ask the dose question, and there are now two randomized trials37,38 showing that higher doses of photon radiation increase biochemical no evidence of disease (bNED) survival compared with lower doses in the treatment of prostate cancer. The development of IMRT also enables us to test a new type of hypothesis concerning dose localization. For instance, for the same toxicity, is it better to give a homogenous target dose or higher doses to regions of the target predicted to be resistant at the expense of lower doses to regions not predicted to be resistant? However, we must also face the possibility that if such trials show no clinical improvement from the doses or dose localizations permitted by the new technology, then the new approach may not be useful in that setting. In other words, although head-to-head trials of IMRT versus 3-dimensional are probably not feasible, we may conclude that in certain clinical settings the benefits provided by IMRT are not measurable and that 3-dimensional therapy would be sufficient. We see the development pathway for new technologies to begin with the validation of the principle by realistic “drylaboratory” calculation (including estimates of geometric uncertainties and organ motion) and initial phase I and phase II trials to set the parameters for the dose questions (either higher tumor dose or lower normal-tissue dose) that will subsequently be answered in a randomized trial. Therefore, we would strongly encourage the use of IMRT on prospective trials until the randomized dose trials can be constructed. This strategy has, unfortunately, not been adopted in the United States, and there appears to be widespread use of IMRT off study in situations in which the clinical benefit is far from proven but the cost of treatment has been increased.
Prostate Cancer Prostate cancer would seem to be an attractive site for the consideration of IMRT. There is strong evidence that increas-
R.K. Ten Haken and T.S. Lawrence ing dose increases bNED survival,37-39 yet dose escalation is difficult because of rectal and bladder toxicity. Because the prostate and seminal vesicles represent a concave target with respect to the dose-limiting OAR of the rectum, IMRT would be anticipated to permit dose escalation with improved outcome. Given the strong rationale, it is disappointing that there are so few systematic reports on the late toxicity of IMRT compared with 3-dimensional conformal therapy in the treatment of prostate cancer. Although a number of studies have evaluated acute effects (eg, Teh and coworkers40), the only large reported series with reasonable follow-up is that of Zelefsky and colleagues,41 which will therefore be examined in some detail. They described the results of treatment of 772 patients with a spectrum of clinically localized prostate cancers, 90% of whom received 81 Gy and the remainder 86.4 Gy. This was a minimum PTV dose, except for the region in which the PTV overlapped with the rectum; dose to this region was limited to 88% of the prescription dose (71 and 76 Gy, respectively). Only the initial 11% of the patients was treated on a prospective trial. The overall result of this study was that only about 0.5% of patients had late grade 3 genitourinary (GU) or gastrointestinal (GI) toxicity. Although the follow-up period was short, there was no suggestion that bNED survival was compromised by the application of this new technology. These results appear to be modestly superior to the recent study by the Radiation Therapy Oncology Group (RTOG) of the results of treatment at “level 5” of a prostate dose escalation trial (RTOG 9406). At level 5, the minimum target dose was 77.9 Gy, and the median target dose was 81.4 Gy. In this study, about 3.7% and 3.2% of the patients evidenced late grade 3 GU or GI toxicity.42 Therefore, although modern 3-dimensional conformal therapy can deliver doses in the range of 78 to 80 Gy with moderate acute but low long-term toxicity, IMRT, at least as delivered at the Memorial Sloan Kettering Cancer Center, New York, NY, appears to offer a modest decrease in toxicity.
Head and Neck Cancer In the case of head and neck cancer, the goal of treatment with IMRT for most clinical trials has been to reduce normal tissue toxicity while preserving tumor control.43-45 Before investigators undertook detailed studies of improved dose conformality to decrease toxicity, the focus of head and neck research was on fractionation and the role of combined radiation and chemotherapy. Although hyperfractionated and accelerated radiation approaches have been shown to be superior to once daily radiation alone,46 it is not yet clear whether this difference is maintained in patients receiving chemotherapy. Thus, there are at least two “standard” approaches using combined chemotherapy and radiation for the treatment of patients with unresectable disease: one using twice daily radiation and another using once daily radiation (for meta-analysis, see Pignon and coworkers47). It is not the purpose of this review to focus on this question, but, given the time and labor involved in IMRT delivery and the absence
Intensity-modulated radiation therapy of data that twice-daily radiation with chemotherapy is superior, current IMRT approaches have tended to focus on oncedaily radiation with chemotherapy. For patients with unresectable head and neck cancers treated once daily (with chemotherapy), the gross tumor typically receives a dose of 70 Gy in 2 Gy fractions, areas at risk for subclinical disease may receive 46 to 50 Gy, and regions at high risk for subclinical disease receive 60 to 64 Gy. These doses would be achieved by using successive boosts, and thus all treatment would be in 2-Gy fractions. Two main clinical strategies have been used to implement and, hopefully, improve on this general approach. Each tries to produce the greatest possible difference between the dose to the tumor and the adjacent parotid glands and spinal cord. The first involves keeping the gross tumor dose at 2 Gy per fraction. This requires treating the regions at risk for subclinical disease at lower doses per fraction and estimating a biocorrection for fraction size. This approach would be expected to produce the same tumor control as conventional chemoradiation approaches, with the “pure” goal of decreased toxicity. The risk in this strategy is that subclinical disease might receive insufficient dose, depending on the accuracy of biocorrection for the lower dose per fraction. A second approach has proposed using greater than 2 Gy per fraction (in the range of 2.2-2.4 Gy) to the tumor. Here the goal is to use IMRT to accelerate treatment without substantially increasing toxicity. The risk to this approach is that it could be substantially more toxic than standard therapy, depending on how well improved dose distributions of IMRT can translate into decreased toxicity when combined with chemotherapy. Both approaches share a risk of marginal misses that can occur when more conformal delivery is attempted. With respect to the first strategy described previously, there are now clinical studies from a number of institutions that suggest that IMRT can be used to spare parotid function while maintaining local-regional control rates. Although we are not aware of any completed randomized trials between IMRT and non-IMRT therapies, preliminary results from an ongoing study48 suggest that patients treated by using IMRT had less xerostomia than those treated by using 2-dimensional radiation therapy at 6 weeks (P ⬍ .002) and 6 months (P ⬍ .06) after treatment. A growing number of single-institution studies49-51 all have sufficient numbers of patients (⬎50) and median follow-up (⬎3 years) showing local failure rates in the range of 10% to 15%, few marginal failures, and preservation of parotid function. It would be anticipated that detailed studies of these marginal failures will improve target definition and improve on these results. Although these clinical findings are very encouraging, there are several caveats to this conclusion. First, modest but potentially significant clinical differences in control rates between more standard approaches and IMRT cannot yet be definitively assessed because of the heterogeneity of sites, stages, and other treatments found in all head and neck series. Second, attempts to take advantage of the greater conformality of IMRT requires a detailed understanding of head and neck anatomy that was not a routine part of clinical training for most radiation oncologists graduating more than
229 3 years ago. New training will be required for most radiation oncologists who wish to apply this technology appropriately. Third, the relationship between parotid salivary flow and the subjective sense of xerostomia may be weaker than was originally anticipated, and organs such as the minor salivary glands (which are not always spared with IMRT) may play an important role in the patient’s quality of life. Fourth, other toxicities that have not yet been addressed may affect quality of life to an equal or greater extent than xerostomia, although initial clinical efforts suggest that IMRT may be able to decrease this toxicity as well.45 Thus, the overall benefit of IMRT based on OARs of the spinal cord and parotids is still not fully defined. Much less is known about the second strategy of using IMRT for dose escalation. The most recent publications concerning the clinical outcomes20,22 suggest that escalation to 2.3 to 2.4 Gy fractions may be possible with radiation alone, but whether this is tolerable with concurrent chemotherapy is not determined. Likewise, there are insufficient data to assess the effect of this approach on local regional tumor control. It would seem that this approach should be limited to prospective clinical trials.
Other Sites A number of sites in addition to head and neck and prostate cancer have been explored, although few long-term clinical results are available. With regard to breast cancer, a randomized trial has been conducted comparing 2-dimensional radiotherapy with 3-dimensional intensity-modulated treated using static fields. The preliminary results of this study have been published in abstract form52 and will soon be submitted for publication (J Yarnold, personal communication, January, 2006). The results show a clinically and statistically significant reduction in the probability of change in breast appearance and palpable induration in the group allocated 3-dimensional dosimetry delivered via multiple static fields. No long-term results of treatment are available for patients receiving IMRT for gynecologic cancers, but some evidence suggests that acute toxicity may be decreased.53 Clinical data from patients receiving treatment for gliomas and lung cancer are too preliminary to permit analysis.
Conclusions IMRT with optimization in planning can be viewed as a technology that enables us to better achieve the goals of treatment planning that we have always had including (1) maximizing target dose, (2) improving target homogeneity, and (3) avoiding organs at risk (although, as pointed out earlier, it may not be able to do all 3 at once). The opportunities to avoid critical normal tissues and to arrange dose within the target to achieve specified ends is greatly enhanced over what can be achieved even with very good 3-dimensional planning. However, these goals can only be accomplished by paying meticulous attention to technical aspects of planning, localization, and delivery. In the case of prostate cancer and head and neck cancer, current evidence does suggest that IMRT permits us
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230 to safely increase dose (in the former) and to protect the parotid glands (in the latter). Although the clinical data on intracranial tumors is limited, the ability to image tumors and critical normal structures, combined with the excellent immobilization that can typically be achieved, suggest this should be a fruitful site for study. Other tumor types, such as lung, breast, and gynecologic cancers, present issues of target definition, localization, and organ motion that would seem to require additional investigation before IMRT becomes standard. Unfortunately, only a small fraction of patients receiving IMRT are currently treated on prospective trials, which is the only way to begin to determine if the hypothetical clinical benefits are actually realized. Given the greater expense of IMRT, it will be critical to better quantify its benefit in future studies.
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