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Future developments in external beam radiotherapy will be unlikely to significantly improve treatment outcomes over those currently achieved with 3D‐conformal and IMRT treatments

2007; Wiley; Volume: 34; Issue: 8 Linguagem: Inglês

10.1118/1.2747051

2473-4209

R. J. Schulz, Dirk Verellen, Colin G. Orton,

Radiation Therapy and Dosimetry

Arguing against the Proposition is Dirk Verellen, Ph.D. Dr. Verellen is Professor, Vrije Universiteit Brussel (VUB), and director of the Medical Physics Group in the Department of Radiotherapy, Universitair Ziekenhuis, Brussels, Belgium. He received his M.Sc. in solid-state physics from the University of Antwerp, Belgium, and his Ph.D. in medical sciences from the VUB. In addition to his educational duties at the VUB in Medical Physics, he is also guest professor at the Europese Hogeschool, Brussels, in the training program for Radiation Technologists and course director for Image-guided Radiation Therapy at the ESTRO European School of Radiotherapy. He is author of over 40 peer-reviewed scientific papers and editor or contributing author of several books. His main interest is in the clinical implementation of conformal radiotherapy and image-guidance. He serves on the Board of Editors of Medical Physics, and chairs the Working Group on New Technologies for the Organization of European Cancer Institutes. He is a member of the Nederlandse Commissie voor Stralingsdosimetrie sub-committee on Guidelines for Stereotactic Treatments, the AAPM Task Group 101 on Stereotactic Body Radiosurgery, and the Belgian Quality Audit Programme for Radiotherapy. The seemingly frantic development of technology for radiation therapy that followed close on the heels of 3D-CRT and IMRT continues unabated for reasons that are at best speculative. However, two things are clear: (a) there is no evidence that IGRT, respiratory gating, electronic portal imaging, ultrasonic guided patient positioning, nor even IMRT itself have led to increased survival times; (b) the cost of radiation therapy has risen in parallel. In what can best be described as a blind gallop towards increasingly more precise means of tumor localization, physicists and manufacturers appear ignorant of the vast experience with cobalt-60, linear accelerators, and betatrons that began accumulating in the 1950's. Do they actually believe that failures to achieve local control were due to consistent patterns of geographical miss, or that a gain in the therapeutic ratio is all it will take to improve outcomes? If future developments in radiation therapy are to significantly improve outcomes, then these developments must impact on those cancers that cause the largest numbers of deaths which, in the USA, are: lung (160 390), digestive system (134 710), breast (40 910), and prostate (27 050).1 From 1977–2002, the five-year relative survival for all stages of lung cancer went from 13% to 16%.1 Surgical resection remains the treatment of choice, while radiation is employed mainly for the medically inoperable but with much poorer results.2 As for dose escalation, using 3D-CRT Kong et al.3,4 found that in going from , overall survival in a small number of patients increased by a statistically insignificant amount, 22% to 28%, but with acceptable levels of toxicity. Digestive tract cancers are treated mainly by surgical resection with pre- or post-operative irradiation and chemotherapy. Relative five-year survivals range from 65% for colorectal, 14% for esophagus, to 5% for pancreatic cancers.1 When viewed in terms of the overall treatment strategies for lung and digestive tract cancers, there is nothing to suggest that techniques beyond CT localization and 3D-CRT will improve survival. The five-year relative survival for breast cancer increased from 75% to 89% over the period 1977–20021 due mainly to screening and the detection of carcinoma in situ, and small lesions having a low incidence of positive nodes. Radiation following lumpectomy has reduced local recurrence and most of the currently employed irradiation techniques are equally efficacious in reducing cardiac morbidity. Whether by prostatectomy or 3D-CRT, the current ten-year cause-specific survival for early-stage prostate cancer is 90% or better.5,6 Late-stage disease does not fare as well but this is hardly due to poor tumor localization. Since this is a disease of older men, 80–85% of men with prostate cancer die of other causes.7 There is little reason to believe that further refinements in tumor localization, more precisely defined dose distributions, or dose escalation, will affect current levels of outcome. Despite the myriad technical advances over the past decade, their contributions to survival rates are undetectable, albeit there have been reduced levels of toxicity in some cases. It is far more likely that improvements will come from sensitizing drugs and chemoradiation. The Proposition is without doubt true and, in fact, need not be limited to future developments only. A review of the Swedish registry8 reveals that cure rates have not improved over the last 30 years stage-by-stage for most solid tumors. Relative survival rates in NSCLC are identical for patients diagnosed between 1964–1966 and 1994–1996, regardless of technological improvements. For breast cancer an improvement has been observed, but this might well be attributed to the Will Rogers phenomenon in that tumors are discovered sooner and tumor volume has decreased stage-by-stage, apparently improving outcome.9 Apart from the introduction of CT-based dose planning, radiation oncology never experienced revolutionary steps forward in the improvement of treatment outcomes during the past decades. The history of radiotherapy has followed a slow but distinct path of evolutions, each of which represented some improvement. We have to acknowledge that there exist almost no randomized trials with clinically relevant end-points (such as overall survival) proving an evidence-based benefit from these technical innovations, although complications have been reduced. As cancer becomes a chronic disease, quality of life should be reconsidered in the ranking of relevant end-points. Returning to the example of NSCLC, the collaborative group10 showed that chemotherapy combined with radiotherapy outperformed radiotherapy alone, but introducing a different fractionation schedule (CHART) made an even larger improvement in outcome (without altering the chemotherapy).11 The latter, however, came at the cost of complications. Imagine the results if these studies would have been performed with the latest IGRT technology: improved outcome with reduced complication rate. Developments in radiotherapy are technology driven: energies escalated from kV to MV; customized blocks replaced standard shielding which, in turn, were replaced by computer-controlled MLCs; introduction of arc-therapy; 3D-CRT has given way to IMRT; and heavy ions promise some interesting radiobiological advantages. One can say that radiation oncology represents a perfect example of evolution theory in that the most adapted technology survived. The proposition suggests that the current state-of-the-art in 3D-CRT and IMRT has reached its summit. But is this true? As the precise dose distributions produced by 3D-CRT and IMRT are less forgiving in terms of treatment uncertainties these techniques will never reach their true potential without proper image-guidance, and it seems fair to say that the evolution still continues. Finally, most technological innovations focussed on improving spatial selectivity, and IMRT combined with IGRT might indeed reveal the limits that can be realized with external photon beam delivery. However, some challenges remain: (1) photons might not suffice to combat radio-resistant tumors and heavy ions might present a possible technological improvement; (2) tumor delineation currently represents the weak link in the treatment chain. New imaging modalities will help to avoid inter-observer variation12 and provide increased functional/biological information about the tumor in order to focus the treatment more efficiently. These developments will help us to “paint dose by numbers” by acknowledging the heterogeneous nature of tumors, which has so far been neglected by delivering homogeneous dose distributions. As always, with each step forward we realize there is an increased number of things we know too little about. We continue to evolve. In his opening statement, Dr. Verellen points out that treatment outcomes have improved little over the past . He suggests that “radiotherapy has followed a slow but distinct path of evolutions, each of which represented some improvement” but then goes on to acknowledge that there is scant evidence linking technical improvements with longer survival time. These observations point to an issue that should be of great concern to physicians and physicists alike: if technical developments over the past decade have resulted in improved outcomes, then the extent of these improvements should be documented. Admittedly, such documentation will be difficult to come by. When increases in survival are likely to be small, which they most certainly are in the case of technical developments, randomized-prospective trials are often impractical because they require large numbers of closely matched patients accrued over many years. On the other hand, retrospective studies, such as four-field box versus IGRT for the treatment of prostate cancer, compare what was done yesterday with something that is being done today. Such studies are on shaky ground because patient management steadily improves, there are periodic changes and inter-hospital variations in how the disease is staged, expanded screening results in the detection of earlier-stage, more curable disease, and newer chemotherapy regimens have come into place. Lacking such documentation, hypothetical arguments that favor the adoption of complex and costly systems have gained wide acceptance by physicists and physicians alike. This acceptance requires a leap of faith that is anything but scientific, while taking our attention away from the critical issue of costs versus benefits. Until the benefits of technical developments are demonstrated, their higher rates of reimbursement cannot be justified on clinical or moral grounds, and such reimbursements rejected by insurers as well as providers. Dr. Schulz misses the point in that adoption of new technology is not a blind gallop but rather an evolution driven by the willingness to improve quality of health care for each patient. Surgeons are not challenged to initiate randomized trials proving possible benefit of superior scalpels, nor did we feel compelled to prove the benefit of portal films (it was accepted as common sense and good QA). Compared to chemotherapy, radiotherapy is modest in cost (5.6% of cancer care costs) and far more cost-effective.13 The vast experience that Dr. Schulz refers to cannot compare to results obtained with the precise dose delivery achievable today. And yes, I would argue that the large amount of failure in local control could be attributed to geographical miss and poor therapeutic windows due to the need for large treatment margins. It is with the clinical introduction of IGRT that we start to understand the true concept of margins and organ motion. Referring to the example of lung cancer, Dr. Schulz compares apples and oranges with surgical resection of operable, and radiotherapy of inoperable, lung cancer. Recent studies show comparable results between surgery and radiotherapy for similar populations, with less co-morbidity for radiotherapy.14 For breast cancer, Dr. Schulz argues that improvements will more likely come from chemotherapy, yet provides a nice example where developments in chemo- and radiotherapy need careful synchronization. Herceptine (trastuzumab) is a case in point offering 52% reduced risk of recurrence (five months increased survival), with a factor of four increase in cardiotoxicity.15–17 A safe combination of this drug with radiotherapy requires a highly accurate treatment delivery that spares cardiac tissue as much as possible. Dr. Schulz's final statement that improvement will more likely come from sensitizing drugs and chemotherapy is at best true only if this is combined with an optimal synergy between surgery and state-of-the-art radiotherapy.