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Journal of Clinical Oncology, Vol 25, No 8 (March 10), 2007: pp. 921-923 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.10.9082
Think Globally, Act LocallyUniversity of Michigan Medical Center, Ann Arbor, MI
Helen F. Graham Cancer Center, Newark, DE
Louisiana State University Health Science Center and the Feist-Weller Cancer Center, Shreveport, LA
Thomas Jefferson University, Philadelphia, PA This special issue of the Journal of Clinical Oncology is devoted not to the elimination of global warming, but to advances in the local therapy of cancer. There are a number of reasons for us to be concerned about local control. The simplest is surgical resection alone cures many thousands of patients with early-stage cancers each year. In addition, there is now strong evidence from randomized trials that demonstrate that other local therapies (especially when combined with chemotherapeutic agents used as sensitizers) can lead to long-term survival for patients with locally advanced cancers, including gliomas, head and neck, lung, cervix, and prostate (in the case of radiation therapy), and liver (in the case of chemoembolization or radiofrequency ablation). In other instances, improvements in local therapy permit healthy tissue to be spared, such as avoiding xerostomia in the treatment of head and neck cancer, breast conservation in the treatment of breast cancer, and sphincter sparing surgery for rectal cancer. Thus, although it is true that many patients will succumb to systemic disease, improvements in local therapy have the potential to improve both the survival and quality of life of many patients who develop malignancies. This special issue begins with a series of articles on how state-of-the-art radiation therapy and interventional radiology is administered in 2007. Our goal in soliciting these articles was to describe the key principles of these approaches, so as to better appreciate the framework of these fields. The last set of articles focuses on specific disease sites so as to illustrate how these principles of local therapy have been applied to improve the outcome of treatment. The issue begins with a discussion by Drs Galvin and De Neve1 of the overall concepts of radiation therapy treatment planning and delivery in the age of intensity modulated radiation therapy (IMRT). IMRT is the result of a series of technical improvements that have occurred over the past 20 years. Standard two-dimensional radiation therapy used radiation beams of constant intensity. Initial work in three-dimensional conformal therapy permitted these fields to be shaped to match the target much more accurately than two-dimensional treatment, and could use beams that were not confined to the axial plane. The multileaf collimator, which replaced cut blocks for aperture shaping, permitted the intensity of the beam to be altered, and the use of multiple leaves and sophisticated "forward" planning permitted very conformal dose distributions to be administered. The key step came from the development of sophisticated software that permitted inverse planning, meaning that the radiation oncologist specifies the dose distribution, and the plan is calculated to deliver it. Additional software is required to specify how the leaves of the collimator need to move in order to deliver this dose. These developments in both optimization and delivery are particularly powerful in treating "the donut, but not the hole" (shaping concave dose distributions around critical targets). In addition, they offer the potential for dose painting, which is the potential to match the dose distribution to high- and low-risk parts of the tumor that could be revealed by new advances in functional imaging. The authors have included a list of the most widely used new devices for delivering these treatments. This discussion reveals that, although there are differences in device construction, the actual doses that can be delivered are fairly similar. In order to take advantage of the these improved potential dose distributions, it is crucial that the biologic target can be defined as accurately as possible, and the dose can be delivered to this well-defined target in patients who breathe and move. The first challenge is addressed by Balter and Kessler, 2 who describe how to bring advanced functional and molecular imaging into the treatment planning. In recent years, these concepts have developed beyond simply transferring information from a magnetic resonance image to a treatment-planning computed tomography scan. The goal of work in this field is to develop a four-dimensional dynamic model of the patient that incorporates anatomic and biologic imaging and includes potential patient and target motion as well as changes that can occur during a course of treatment. Drs Dawson and Jaffrey3 ask how to assure, given this dynamic model, that dose is delivered accurately. Standard radiation delivery is guided by skin marks that are aligned to lasers that are in a fixed orientation to the treatment unit. Although this can provide a reasonable degree of accuracy, the safe and effective application of techniques described herein can often require a greater degree of accuracy than skin marks can provide. Dawson and Jaffrey describe image-guided radiation therapy (IGRT), in which daily assessment of the target location is performed on the treatment unit. This can be accomplished in a number of ways, such as by placing fiducial markers (for instance, radio-opaque gold seeds) and performing portal imaging, or by acquiring computed tomography images on the treatment unit itself. IGRT permits a level of accuracy that is significantly better than was possible previously, and has made it possible to consider the delivery of higher doses of radiation than might otherwise be safely given. An application of IGRT is in the delivery of stereotactic body radiation (SBRT), the use of which is reviewed by Timmerman and colleagues.4 SBRT is an attempt to ablate tumors using five or fewer fractions, and is derived from the successful experience of using stereotactic radiation to treat brain metastases. The concept underlying this treatment is the opposite of fractionated radiation typically used. The goal of fractionation is to convert the slightly greater killing of cancer cells than healthy cells that results from a single fraction to a large therapeutic index by repeating that single fraction 20 to 40 times. In stereotactic treatment, the goal is ablation, without a real attempt made to achieve a therapeutic index other than by careful tumor localization. However, in contrast to the brain, where immobilization and tumor localization can be accomplished by the use of a head frame, immobilization and localization with external fixation devices cannot be as accurate for lung and liver tumors. SBRT works because, for tumors smaller than approximately 5 cm, only small portions of the lung and liver will be damaged by the ablative dose. Although the role of SBRT is still being established, it is clearly capable of producing long-term local control of small lung and liver tumors. The ultimate method of delivering conformal radiation is the particle beam. Particle beams (protons and carbon ions) have the advantage over photons that they stop after they have traveled a controlled distance. Carbon has an additional potential advantage in that it can kill hypoxic cells that exist inside of tumors far more efficiently that either photons or protons. Drs Schultz-Ertner and Tsujii5 review the clinical literature on the application of charged particles. Unfortunately, proton and carbon beam facilities are far more expensive than linear accelerators (approximately $150, $250, and $5 million, respectively). Dr Brada and colleagues6 raise the question of whether there are sufficient clinical data to support this kind of expenditure. The questions raised by Dr Brada and colleagues are unique to radiation oncology and will need to be answered soon (or, perhaps, should have been answered yesterday). In medical oncology, there is a need to compare drug treatment A to drug treatment B. It is not possible to determine which is better without carrying out a randomized trial. In radiation oncology, one can know, based on physics that protons deliver a better dose distribution than photons or that IMRT is superior to three-dimensional conformal therapy. If treatment planning and delivery are carried out properly, which can be defined by a set of rules, there is no debate; this is a matter of physics. The big question is: is the clinical improvement worth the added expense? What kind of trial needs to be designed to answer this question? It will be difficult to run a randomized trial in the United States asking whether a treatment that is superior based on physics is worth it. Would patients permit themselves to be randomly assigned to the standard but less expensive therapy? This is clearly an important area for study. The two final articles in the first section are by Dr Willett and his colleagues7 on intraoperative radiation therapy (IORT) and Dr Liapi and colleagues8 on interventional radiology. The former study discusses the basic principles of IORT, which have been known for many years, but includes recent technical improvements that should make it easier to deliver, shorten the extra time spent in the operating room, and presents alternatives to the dedicated IORT suite. The latter study reviews improvements in catheter-based therapies, such as radiofrequency ablation. Advances in image guidance have also enhanced the ability of interventional radiologists to ablate tumors in the liver, and, more recently, in other sites. The second section of this issue delves into the application of these advances in local therapies to the treatment of five disease sites where they have had the greatest effect recently: localized prostate cancer, soft tissue sarcoma, breast cancer, rectal cancer, and head and neck cancer. Many of the specific techniques described herein have been brought to bear on these sites, particularly prostate cancer and head and neck cancer. It is now possible to safely deliver 78 to 86 Gy to the prostate using IMRT guided by IGRT. These higher doses matter. There is now evidence from at least three randomized trials that this higher dose produces an improved progression-free survival (although not yet overall survival) compared with 70 Gy, which is the maximum safe dose of standard doses in the early three-dimensional era.9 In head and neck cancer,10 the thrust of technical improvement has initially been focused on decreasing xerostomia, by decreasing dose to the parotid, while maintaining excellent tumor control. For both prostate and head and neck cancer, an effort is being made to incorporate functional and metabolic imaging, to develop improved target definition, and to use IGRT to assure that highly conformal therapies are accurately delivered. The article by Pister and colleagues11 focuses on multimodality therapy and novel therapies to improve local control in soft tissue sarcoma. Although few data are available concerning the use of IMRT in extremity soft tissue sarcoma, the ability to develop dose distributions that wrap around the bone rather than giving the bone a full dose might decrease the risk of fracture. The articles on partial breast irradiation12 and rectal cancer13 both emphasize how careful patient selection and close cooperation between surgeons and radiation oncologists can allow organ preservation without compromise of local control. In summary, local therapies have shown dramatic improvement over the past few years due to a number of synergistic approaches, including improved treatment planning, imaging, image guidance, and treatment delivery. Perhaps even more importantly, closer collaborations among radiation, medical, and surgical oncology, and both interventional and diagnostic radiology have made therapy more effective and less invasive. A major challenge that still exists is to better understand how to introduce new technologies appropriately. In this context, "Think Globally, Act Locally" might actually be an instruction to us to think harder not only about the local benefits but also about the global costs society incurs from these sophisticated new treatments. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. Author Contributions Manuscript writing: Theodore S. Lawrence, Nicholas J. Petrelli, Benjamin D. Li, James M. Galvin REFERENCES
1. Galvin JM, De Neve W: Intensity modulating and other radiation therapy devices for dose painting. J Clin Oncol 25:924-930, 2007 2. Balter JM, Kessler ML: Imaging and alignment for image-guided radiation therapy. J Clin Oncol 25:931-937, 2007 3. Dawson LA, Jaffray DA: Advances in image-guided radiation therapy. J Clin Oncol 25:938-946, 2007 4. Timmerman RD, Kavanagh BD, Chinsoo Cho L, et al: Stereotactic body radiation therapy in multiple organ sites. J Clin Oncol 25:947-952, 2007 5. Schulz-Ertner D, Tsujii H: Particle radiation therapy using proton and heavier ion beams. J Clin Oncol 25:953-964, 2007 6. Brada M, Pijls-Johannesma M, de Ruysscher D: Proton therapy in clinical practice: Current clinical evidence. J Clin Oncol 25:965-970, 2007 7. Willett CG, Czito BG, Tyler DS: Intraoperative radiation therapy. J Clin Oncol 25:971-977, 2007 8. Liapi E, Geschwind FH: Transcatheter and ablative therapeutic approaches for solid malignancies. J Clin Oncol 25:978-986, 2007 9. Speight JL, Roach M: Advances in the treatment of localized prostate cancer: The Role of anatomic and functional imaging in men treated with radiotherapy. J Clin Oncol 25:987-995, 2007 10. Feng M, Eisbruch A: Future issues in highly conformal radiotherapy for head and neck cancer. J Clin Oncol 25:1009-1013, 2007 11. Pisters PWT, O'Sullivan B, Maki RG: Evidence-based recommendations for local therapy for soft tissue sarcomas. J Clin Oncol 25:1003-1009, 2007 12. Sanders ME, Scroggins T, Ampil FL, et al: Accelerated partial breast irradiation in early-stage breast cancer. J Clin Oncol 25:996-1003, 2007 13. Baxter NN, Garcia-Aguilar J: Organ preservation for rectal cancer. J Clin Oncol 25:1014-1020, 2007
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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