In response to Dr. G. Bauman and Dr. G. Rodrigues

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I. J. Radiation Oncology

● Biology ● Physics

Fig 1. Plot of rectal DVH recommendations.

15. Wachter S, Gerstner N, Goldner G, et al. Rectal sequelae after conformal radiotherapy of prostate cancer: Dose-volume histograms as predictive factors. Radiother Oncol 2001;59:65–70.

IN RESPONSE TO DR. G. BAUMAN AND DR. G. RODRIGUES To the Editor: We are glad to take the opportunity given by the letter by Bauman and Rodrigues, to discuss a few points about the correlation between rectal dose–volume patterns and rectal bleeding previously reported in our recently published article (1). As Bauman and Rodrigues showed in their concise review, the number of investigations reporting correlation between rectal toxicity after 3D conformal radiotherapy (3D CRT) and dose–volume information individually collected from the calculated 3D dose distribution is rapidly increasing. This fact reflects the vital need to define more rational dose–volume constraints in the era of doseescalation for prostate cancer with 3D-CRT and intensity-modulated radiotherapy (IMRT). Given the differences between these studies, well reported by Bauman and Rodrigues, the substantial consistency about the “optimal” constraints suggested by different authors may appear quite amazing. A crucial point concerns the difference between moderate (Grade 2) and severe (Grade 3) toxicity, as the latter has a much higher impact on the quality of life of patients. Our analysis revealed a stronger impact of the “high” dose region (V70) of the rectal DVH when considering Grade 3 bleeding compared to “intermediate” dose levels (V40 – 60); a similar result was found by other investigators (2,3) and was recently confirmed by a further analysis on a very large (⬎500 patients, 45 ⱖ Grade 2 bleeders) patient population pooled from five Italian institutions. These data were fitted by normal tissue complication probability (NTCP) models (4) showing a different behavior of the rectum when considering Grade 2 or Grade 3 bleeding, suggesting that the rectum behaves much more as a serial-like organ when considering Grade 3 bleeding (n ⫽ 0.06; n is the volume effect parameter in the Lyman-Kutcher model [5]). On the other hand, trying to limit the fraction of rectum receiving “intermediate” dose seems to have an impact mainly in reducing the occurrence of Grade 2 bleeding. Another issue raised by Bauman and Rodrigues concerns rectum definition. We believe that a simple and clear anatomical definition of rectum (i.e., from the anus to the point in which it turns into the sigmoid) should be preferred. Within a national working group we were able to assess the impact of inter-institutional variability in contouring the external surface of the rectum following this definition. Our results showed that this “standard” definition is sufficiently robust (6, 7). At this moment, there are no data about interobserver variations in contouring the rectal wall. As the rectal wall is often difficult to see, a larger interobserver variability may be expected. On the other hand, if the rectum is mostly empty (as it is for most patients if a protocol of emptying the rectum before CT simulation is followed), the dose–volume histogram of the rectal wall (DWH) and of the rectum including filling (DVH) are strongly correlated (8). This fact may explain the substantial consistency between most published results using DWH or its surrogates (like normalized dose–surface histograms [NDSH])

Volume 59, Number 3, 2004 and DVH; however, in the case of full rectum the differences between DVH and DWH may be very high. For this reason, we suggested caution in handling DVH of patients with full rectum (9); these patients may tend to experience a larger systematic difference between DVH/DWH at CT simulation and during therapy, due to the reported trend in emptying the rectum as an effect of the radiotherapy (10, 11). These few examples indicate that many points are still to be clarified, especially about the assessment of reliable “confidence levels” around the dose–volume constraints used in our clinical routine. Provided that the cutoff of constraints is clearly outlined in the analysis and possibly obtained in a statistically rigorous manner (i.e., throughout the median values or percentiles), the next issue concerns which cutoff is to be used when data are used prospectively, i.e. to generate IMRT plans. Most suggested dose–volume constraints reported in literature were derived from analyses of large populations with a wide spread of the shape of DVH. This means that the “low-risk” population includes “very good” DVHs while the “high-risk” population includes “very bad” ones; thus, aiming at keeping the DVH slightly below the suggested constraint does not automatically imply that the expected risk of bleeding is really “low”. The possibility of assessing the risk of bleeding starting from the shape of the DVH, through DVH reduction to NTCP or equivalent uniform dose (EUD) would be more suitable and should be preferred during planning optimization. The recently reported values of the parameters for NTCP/EUD calculation (4, 12) may be considered as a starting point which could be refined through further prospective investigations like the one activated in the Italian working group on prostate cancer (AIROPROS01-02) that closed patient enrollment in December 2003. The impact of other comorbidity variables such as diabetes, hypertension, and hormonal therapy (13) should also be better clarified and could reasonably lead to a different definition of dose–volume constraints and, preferably, NTCP/EUD values in subgroups of patients considered to be at higher risk of developing rectal toxicity. In conclusion, reliable constraints mean the possibility of selecting the patients who would truly benefit from the application of more sophisticated techniques such as IMRT and image-guided RT and of driving dose painting by minimizing the risk of missing the target. The availability of image-guided techniques for sculpting the dose distribution around an increasingly optimally defined target, including the possibility of “superboosting” the more resistant portion of the tumor by functional-imageguided radiotherapy (14), opens new challenges concerning the protection of the organs at risk around the prostate primarily the rectum. A more precise knowledge of the radiobiology of the rectum will be crucial in orienting the efforts to increase the therapeutic ratio of prostate cancer through external radiotherapy. CLAUDIO FIORINO, PH.D. Medical Physics H. S. Raffaele Milan, Italy GIUSEPPE SANGUINETI, M.D. Radiation Oncology University of Texas Medical Branch, Galveston, TX RICCARDO VALDAGNI, M.D. AIRO working group coordinator National Institute of Cancer Milan, Italy doi:10.1016/j.ijrobp.2004.02.048 1. Fiorino C, Sanguineti G, Cozzarini C, et al. Rectal dose–volume constraints in high-dose radiotherapy of localized prostate cancer. Int J Radiat Oncol Biol Phys 2003;57:953–962. 2. Boersma LJ, van den Brink M, Bruce AM, et al. Estimation of the incidence of late bladder and rectum complications after high-dose (70 –78 Gy) conformal radiotherapy for prostate cancer, using dose– volume histograms. Int J Radiat Oncol Biol Phys 1998;41:83–92. 3. Pollack A, Zagars G, Starskschall G, et al. Prostate cancer radiation dose response: Results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002;53:1097–1105. 4. Rancati T, Fiorino C, Gagliardi G, et al. Fitting late rectal bleeding data using different NTCP models: Results from an Italian multicentric study (AIROPROS0101). Radiother Oncol 2004; In press. 5. Lyman JT. Complication probabilities as assessed from dose–volume histograms. Radiat Res 1985;104:13–19.

Letters to the Editor 6. Fiorino C, Vavassori V, Sanguineti G, et al. Rectum contouring variability in patients treated for prostate cancer: Impact on rectum DVHs and NTCP. Radiother Oncol 2002;63:249–255. 7. Foppiano F, Fiorino C, Frezza G, et al. The impact of contouring uncertainty on rectal 3D dose–volume data: Results of a dummy run in a multi-centric trial (AIROPROS01-02). Int J Radiat Oncol Biol Phys 2003;57:573–579. 8. Fiorino C, Gianolini S, Nahum AE. A cylindrical model of the rectum: Comparing dose–volume, dose–surface and dose–wall histograms in the radiotherapy of prostate cancer. Phys Med Biol 2003;48:2603–2616. 9. Fiorino C, Cozzarini C, Vavassori V, et al. Relationships between DVHs and late rectal bleeding after radiotherapy for prostate cancer: Analysis of a large group of patients pooled from three institutions. Radiother Oncol 2002;64:1–12. 10. Lebesque JV, Allison D, Bruce AM, et al. Variation in volumes, dose–volume histograms and estimated normal tissue complication probabilities of rectum and bladder during conformal radiotherapy of T3 prostate cancer. Int J Radiat Oncol Biol Phys 1995;33:1109–1119. 11. Hoogeman MS, van Herk M, de Bois J, Muller-Timmermans P, Koper PCM, Lebesque JV. Quantification of local rectal wall displacements by virtual rectum unfolding. Radiother Oncol 2004;70:21–30. 12. Rancati T, Gagliardi G, Cattaneo GM, et al. Late rectal bleeding: Fitting clinical data with different NTCP models. Int J Radiat Oncol Biol Phys 2003;57(Suppl. 1):S392. 13. Sanguineti G, Agostinelli S, Foppiano F, et al. Adjuvant androgen deprivation impacts late rectal toxicity after conformal radiotherapy of prostate cancer. Br J Cancer 2002;86:1843–1847. 14. Xia P, Pickett B, Vigneault E, et al. Forward or inversely planned segmental multileaf collimator IMRT and sequential tomotherapy to treat multiple dominant intraprosatatic lesions of prostate cancer to 90 Gy. Int J Radiat Oncol Biol Phys 2001;51:244–254.

IN REGARD TO THOMADSEN ET AL.: ANALYSIS OF TREATMENT DELIVERY ERRORS IN BRACHYTHERAPY USING FORMAL RISK ANALYSIS TECHNIQUES (INT J RADIAT ONCOL BIOL PHYS 2003;57:1492–1508) To the Editor: The recent publication regarding brachytherapy error by Thomadsen et al. (1) details a much-needed analysis of the limited number of reported cases of such mistakes. The fact that such errors occur will come as no surprise to radiation oncology practitioners. What is surprising is that by pooling reports from the United States as well as internationally, the authors found a total of only 134 reported brachytherapy errors between 1980 and 2001 (averaging 6.1 events annually). Given the uncounted but obviously large number of brachytherapy procedures performed worldwide during this 22-year period, and given the high reporting threshold (termed by the Nuclear Regulatory Commission as a “misadministration”), the cases comprising this report likely represent only the tip of the brachytherapy error iceberg. What is not apparent is how much more lies beneath the surface. Experience would suggest that most brachytherapy treatments are executed correctly, but that mistakes are more common than indicated by Thomadsen’s numbers. Although based upon the best available but admittedly fragmentary data, this report still offers useful insights. The underlying rationale for any such error analysis is to illuminate the origins of mistakes to catalyze refinement of treatment systems and procedures to prevent future errors. From that perspective, Thomadsen’s exhaustive analysis is overly complex: too many diagrammatic tools and competing classifications diffuse the message. 1. The root cause analysis tree examines a specific event and accordingly differs for each case; discerning patterns of error is therefore difficult. Unexplained marginal comment acronyms (HRI, HRV, TM, TD, OK) complicate interpretation of Figure 2. 2. The fault tree focuses on the process rather than any individual event and effectively illustrates error patterns. However, the authors’ highly detailed representation of the mechanisms of possible error in LDR brachytherapy alone requires 10 pages. This tool’s complexity is its own greatest obstacle to usefulness to physicians. 3. The three error taxonomies discussed are weakened by their focus on different ways of categorizing mistakes rather than upon the functional steps within the brachytherapy process itself. These classifications suffer from their use of opaque terminology: uninformative categories such as “deflection” (Rasmussen), “culture” (SMART), and “bounded rationality” (SCOPE) communicate little that is actionable. These models may be well suited to the interests of industrial engineers,

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but they fall short of proving useful to the radiation oncologist or physicist tasked with treating patients. By contrast, the process tree— better known as a cause-and-effect diagram (2), or colloquially as a “fishbone diagram”—is inherently useful by virtue of its succinct illustration of the multiple steps in the brachytherapy treatment process, steps that are immediately understandable to practitioners. The authors’ HDR process tree immediately shows that errors cluster in certain branches: knowing this, appropriate treatment modifications may be made. The conspicuously absent companion LDR diagram would also be of interest. Thomadsen’s report on brachytherapy treatment error is particularly timely given increasing attention to issues of medical error, patient safety, and quality of care (3– 6). Unlike external beam radiation therapy, much brachytherapy is performed without the safeguards offered by increasingly prevalent record and verify systems. Although not providing total protection against treatment mistakes (7), record and verify systems do much to eliminate error in external beam treatment (8). Similar computerized overview and recording of brachytherapy treatment has been introduced with HDR remote afterloading systems, but as documented by this report, mistakes still occur and suggest opportunities for design improvements. As mechanisms of radiation therapy error across the entire continuum of radiation oncology are better characterized and understood, those who design and market radiation therapy systems should focus their efforts on delivering systems that make it easy to do the right thing, but difficult to make mistakes. Radiation oncologists are obligated to implement treatment techniques and procedures toward the same ends. GREGORY A. PATTON, M.D., M.S., M.S., M.B.A. Northwest Cancer Specialists Portland, OR doi:10.1016/j.ijrobp.2004.02.036 1. Thomadsen B, Lin SW, Laemmrich P, et al. Analysis of treatment delivery errors in brachytherapy using formal risk analysis techniques. Int J Radiat Oncol Biol Phys 2003;57:1492–1508. 2. Ishikawa K. Guide to quality control. Tokyo: Asian Productivity Organization, 1982, p 18 –29. 3. Kohn LT, Corrigan JM, Donaldson MS. To err is human: Building a safer health system. Washington, DC: Institute of Medicine Press, 2000. 4. Institute of Medicine Committee on Quality of Health Care in America. Crossing the quality chasm: A new health system for the 21st century. Washington, DC: National Academy Press, 2001. 5. Bates DW, Gawande AA. Improving safety with information technology. N Engl J Med 2003;348:2526–2534. 6. Berwick DM. Errors today and errors tomorrow. New Engl J Med 2003;348:2570–2572. 7. Patton GA, Gaffney DG, Moeller JM. Facilitation of radiotherapeutic error by computerized record and verify systems. Int J Radiat Oncol Biol Phys 2003;56:50–57. 8. Klein EE, Drzymala RE, Williams R, Westfall LA, Purdy JA. A change in treatment process with a modern record and verify system. Int J Radiat Oncol Biol Phys 1998;42:1163–1168.

IN RESPONSE TO DR. PATTON To the Editor: Doctor Patton makes some keen observations in his comments on our paper (1). Indeed, I would assume that the data with which we had to work represented the “tip of the iceberg,” and unfortunately, there is no way at the present to uncover many of the underlying events. Doctor Patton’s main criticism is that the analysis we presented was too complex. (However, the complexity pales when compared with subjects such as intensity-modulate radiotherapy [IMRT], optimization, articles that seldom are criticized on the grounds of complexity). Admittedly, there were many layers to our analysis as we tried to be thorough and tease out what information we could from the limited data available. That was, after all, a research paper, and the results were summarized for those who would rather not dig into the many facets of the study. Doctor Patton addresses two separate issues in his letter: the shortcomings of the article and problems with using the tools presented in the article in a clinical practice. As to his criticism of the article itself, his points are well taken, and I admit to the weaknesses. However, his observations on the difficulties of using the tools understate the case. Yes, the tools are involved and probably beyond what most practicing physicians would be willing to do. Further, experience working with these tools, and novices using them, indicate that the processes have a very long learning curve, and without a fair amount