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Letter to the Editor Clinical evidence that more precisely defined dose distributions will improve cancer survival and decrease morbidity !Received 6 March 2003; accepted for publication 7 March 2003" #DOI: 10.1118/1.1570371$ To the Editor, In a recent letter, Dr. Schulz and Dr. Kagan discuss their pessimistic view that ‘‘More precisely defined dose distributions are unlikely to affect cancer mortality.’’ 1 They introduce the idea of the ‘‘Infinitron,’’ a hypothetical radiation source than can create arbitrary dose distributions within the body. They state that the Infinitron might result in fewer complications, but improvements in survival for the average cancer patient are likely to be imperceptible. They give several supporting arguments, including !a" a perfect radiation source approximates surgery, !b" the dearth of diseasespecific survival data, and !c" the rising cost of unproven technologies. We wish to address each of these points separately. !a" A perfect radiation source approximates surgery. In some cases curative cancer surgical procedures, such as the Whipple procedure for pancreatic cancer resection, carry substantial risk of operative and post-operative morbidity and even mortality including post-operative infections and complications of anesthesia. Many tumors are surgically inaccessible or technically unresectable, or if resectable carry a high risk of collateral damage to surrounding organ systems. Furthermore, a significant fraction of patients referred for definitive radiation therapy, particularly for lung cancer, are medically inoperable due to co-morbid conditions such as compromised cardiac/lung function or obesity. Radiation can succeed where surgery cannot. The perfect radiation source might compete successfully with surgery in many sites. Apart from the associated morbidity described above for surgery, radiation therapy can utilize the differential repair capabilities to kill tumor cells embedded within normal tissue while leaving the normal tissue viable. In surgery, the tumor as well as normal tissue is removed. Furthermore, surgery cannot remove all of the clonogenic cells. The Infinitron and even currently available treatment delivery technology, is a less invasive option to surgery for treating microscopic disease extension or surrounding regional lymphatics which are at risk for tumor recurrence. For example, post-surgery radiation therapy for early stage breast cancer has proven to reduce cancer recurrence over surgery alone, even for patients with negative surgical margins.2–5 !b" The dearth of disease-specific survival data. Though it may be true that no randomized clinical trials showing the benefits of IMRT or proton therapy have yet been reported, nevertheless many clinical studies have described the dose response for both normal tissue and tumors. We will use lung cancer as an example. Several studies have shown a survival advantage for higher dose levels.6 –11 Martel et al.8 estimate 1281 Med. Phys. 30 „6…, June 2003 from their data that to achieve 50% local progression-free survival at 30 months 85 Gy will be required; this dose level is considerably higher than that used routinely in clinics due to the risk of lung complications. These lung complications have been shown to be correlated with mean lung dose !or similar surrogate, such as V 20). 12–17 Thus, there is clinical evidence that technologies which allow increased dose to the tumor while sparing healthy tissue will improve the balance between complications and cure. For lung cancer, the Infinitron !or at least its current closest approximations" is exactly what is needed to increase the poor 15% 5-year survival #Cancer Facts and Figures 2003, American Cancer Soci ety, !http://www.cancer.org/downloads/STT/CAFF2003PW Secured.pdf"$ for lung cancer sufferers. !c" The cost of unproven technologies. Any ‘‘new’’ technology is likely to be more expensive than the currently available mass-produced devices to which it is compared, at least initially. However, given the capabilities of modern engineering design and manufacturing, such new devices may not always be more expensive, especially if their market grows as they replace older generation systems. Let physicists and physicians investigate high risk/high return research, and leave it to the engineers to transfer the successful scientific innovations into practical, useful and economical devices. We agree with Schulz and Kagan that the ultimate proof of any new technology is through randomized clinical trials. However, this should not discourage researchers from performing and publishing treatment planning studies !thought experiments" to estimate the potential clinical significance of devices, such as magnetic dose focusing units, before they are made. In fact, these treatment planning studies provide some data that is necessary to perform such costbenefit analyses. In summary, we applaud and support those researchers working in the areas of magnetic dose focusing, advanced image-guided therapy, molecular imaging, Monte Carlobased dose calculation, IMRT, respiratory gating/breathhold/4D methods, proton therapy, etc. Though the Infinitron does not yet exist, all of the aforementioned research efforts are bringing us closer to this goal. 1 R. J. Schulz and A. R. Kagan, ‘‘More precisely defined dose distributions are unlikely to affect cancer mortality,’’ Med. Phys. 30, 276 !2003". 2 B. Fisher, S. Anderson, C. K. Redmond, N. Wolmark, D. L. Wickerham, and W. M. Cronin, ‘‘Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer,’’ N. Engl. J. Med. 333, 1456 –1461 !1995". 3 G. Liljegren, L. Holmberg, J. Bergh, A. Lindgren, L. Tabar, H. Nordgren, and H. O. Adami, ‘‘10-Year results after sector resection with or without 0094-2405Õ2003Õ30„6…Õ1281Õ2Õ$20.00 © 2003 Am. Assoc. Phys. Med. 1281 1282 P. J. Keall and J. F. Williamson: Letters to the Editor postoperative radiotherapy for stage I breast cancer: A randomized trial,’’ J. Clin. Oncol. 17, 2326 –2333 !1999". 4 R. M. Clark, T. Whelan, M. Levine, R. Roberts, A. Willan, P. McCulloch, M. Lipa, R. H. Wilkinson, and L. J. Mahoney, ‘‘Randomized clinical trial of breast irradiation following lumpectomy and axillary dissection for node-negative breast cancer: An update. 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Oetzel, U. Spahn, M. V. Graham, R. E. Drzymala, J. A. Purdy, A. S. Lichter, M. K. Martel, and R. K. Ten Haken, ‘‘Radiation pneumonitis as a function of mean lung dose: An analysis of pooled data of 540 patients,’’ Int. J. Radiat. Oncol., Biol., Phys. 42, 1–9 !1998". 13 M. V. Graham, J. A. Purdy, B. Emami, W. Harms, W. Bosch, M. A. Lockett, and C. A. Perez, ‘‘Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer !NSCLC",’’ Int. J. Radiat. Oncol., Biol., Phys. 45, 323–329 !1999". 14 M. L. Hernando, L. B. Marks, G. C. Bentel, S. M. Zhou, D. Hollis, S. K. Das, M. Fan, M. T. Munley, T. D. Shafman, M. S. Anscher, and P. A. Lind, ‘‘Radiation-induced pulmonary toxicity: A dose-volume histogram analysis in 201 patients with lung cancer,’’ Int. J. Radiat. Oncol., Biol., Phys. 51, 650– 659 !2001". 15 D. Oetzel, P. Schraube, F. Hensley, G. Sroka-Perez, M. Menke, and M. Flentje, ‘‘Estimation of pneumonitis risk in three-dimensional treatment planning using dose-volume histogram analysis,’’ Int. J. Radiat. Oncol., Biol., Phys. 33, 455– 460 !1995". 16 Y. Seppenwoolde, J. V. Lebesque, K. de Jaeger, J. S. Belderbos, L. J. Boersma, C. Schilstra, G. T. Henning, J. A. Hayman, M. K. Martel, and R. K. Ten Haken, ‘‘Comparing different NTCP models that predict the incidence of radiation pneumonitis,’’ Int. J. Radiat. Oncol., Biol., Phys. 55, 724 –735 !2003". 17 E. D. Yorke, A. Jackson, K. E. Rosenzweig, S. A. Merrick, D. Gabrys, E. S. Venkatraman, C. M. Burman, S. A. Leibel, and C. C. Ling, ‘‘Dosevolume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy,’’ Int. J. Radiat. Oncol., Biol., Phys. 54, 329–339 !2002". Paul J. Keall and Jeffrey F. Williamson Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia 23298