- Email: [email protected]
In Reply to Drs. Cheung and Schulz and Kagan
Int. J. Radiation Oncology Biol. Phys., Vol. 70, No. 2, pp. 645–647, 2008 Copyright Ó 2008 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/08/$–see front matter
LETTERS TO THE EDITOR THE NEED AND PROSPECT OF INDIVIDUALIZED EXTERNAL BEAM RADIOTHERAPY DOSE ESCALATION BEYOND 80 GY TO TREAT PROSTATE CANCER: IN REGARD TO EADE ET AL. (INT J RADIAT ONCOL BIOL PHYS 2007;68:682–689)
COMMENTARY ON DOSE ESCALATION AND BIOCHEMICAL FAILURE IN PROSTATE CANCER: IN REGARD TO EADE ET AL. (INT J RADIAT ONCOL BIOL PHYS 2007;68:682–689) To the Editor: Based on a retrospective study, Eade et al. (1) recommend that doses of $80 Gy be administered for the treatment of prostate cancer. The basis for this recommendation was their observation that higher doses reduce the probability of biochemical failure and the incidence of distant metastases. Specifically, the 1,530 men included in their study were divided into four dose groups: \70 Gy, 70–74.9 Gy, 75–79.9 Gy, and $80 Gy. Using the Phoenix criterion, Eade et al. (1) observed that the 5-year freedom from biochemical failure rate for each of the four groups increased as the dose increased: 70%, 81%, 83%, and 89% respectively. All well and good for freedom from biochemical failure; however, when it comes to the proportion of men with freedom from distant metastases at 5 and 10 years, the effect of dose escalation is obscure, with corresponding rates of 96% and 93%, 97% and 93%, 99% and 95%, and 98% and 96%. Given that 55% of the $80-Gy group had Gleason scores .6 and 98%, 80%, and 81% of the lower dose groups had scores in the range of 2–6, it could be that $80 Gy should be given to men with Gleason scores .6. However, the authors’ freedom from distant metastases results for the three lower dose groups were essentially the same, suggesting, if anything, that 70 Gy is sufficient. It seems to us that a patient’s survival, regardless of how defined, provides a better measure of a treatment’s efficacy than the subsequent prostate-specific antigen levels. Because greater doses inevitably increase the probability of gastrointestinal and genitourinary toxicities and 80–85% of prostate cancer patients die of other causes, a balance should be struck between the potential benefits of dose escalation and the patient’s quality of life. The recommendation of Eade et al. ‘‘that the vast majority of patients should receive $80 Gy’’ should be tempered by consideration of the myriad clinical and social factors that are unique to each and every patient.
To the Editor: Data are accumulating, including from the study by Eade et al. (1), that doses .80 Gy might provide additional improvement in treatment outcome for intermediate- and high-risk prostate cancer patients. What is much less clear is whether the entire prostate should receive the additional dose. The rates of rectal and genitourinary side effects associated with prostate cancer external beam radiotherapy are reasonably low at present. However, unless the doses to these normal tissues are maintained near the present level, the risks of rectal and urinary toxicity, albeit mostly low grade, are projected to increase steeply (2, 3). Also, longer term data have shown that the incidence of urinary toxicity, unlike rectal toxicity, continues to increase even after 5 years of follow-up (3, 4). Radiation-induced erectile dysfunction (5, 6) is another severe and common side effect that might limit dose escalation. Thus, treating the entire prostate with a margin .80 Gy might risk increasing normal tissue toxicity. Along this line, the alternative of directing the additional doses only to specific intraprostatic regions is worth considering because this will add smaller doses to the surrounding normal tissues (7). Furthermore, novel imaging techniques might allow us in the future to monitor the physiology of the prostate cancer during a course of radiotherapy (8, 9). Clearly, much more research is needed. This approach, however, holds the promise of individualizing the next phase of prostate cancer external beam dose escalation to only the radiation-resistant areas in the prostate. M. REX CHEUNG, M.D., PH.D. Department of Radiation Oncology University of Texas M.D. Anderson Cancer Center Houston, TX doi:10.1016/j.ijrobp.2007.08.001 1. Eade TN, Hanlon AL, Horwitz EM, et al. What dose of external-beam radiation is high enough for prostate cancer? Int J Radiat Oncol Biol Phys 2007;68:682–689. 2. Tucker SL, Cheung R, Dong L, et al. Dose–volume response analyses of late rectal bleeding after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2004;59:353–365. 3. Cheung MR, Tucker SL, Dong L. Investigation of bladder dose and volume factors influencing late urinary toxicity after external beam radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2007;67: 1059–1065. 4. Gardner BG, Zietman AL, Shipley WU, et al. Late normal tissue sequelae in the second decade after high dose radiation therapy with combined photons and conformal protons for locally advanced prostate cancer. J Urol 2002;167:123–126. 5. Selek U, Cheung R, Lii M, et al. Erectile dysfunction and radiation dose to penile base structures: A lack of correlation. Int J Radiat Oncol Biol Phys 2004;59:1039–1046. 6. Roach M, Winter K, Michalski JM, et al. Penile bulb dose and impotence after three-dimensional conformal radiotherapy for prostate cancer on RTOG 9406: Findings from a prospective, multi-institutional, phase I/II dose-escalation study. Int J Radiat Oncol Biol Phys 2004;60: 1351–1356. 7. van Lin EN, Futterer JJ, Heijmink SW, et al. IMRT boost dose planning on dominant intraprostatic lesions: Gold marker-based three-dimensional fusion of CT with dynamic contrast-enhanced and 1H-spectroscopic MRI. Int J Radiat Oncol Biol Phys 2006;65:291–303. 8. Pickett B, Kurhanewicz J, Coakley F, et al. Use of MRI and spectroscopy in evaluation of external beam radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2004;60:1047–1055. 9. Li C, Liengsawangwong R, Choi H, et al. Using a priori structural information from magnetic resonance imaging to investigate the feasibility of prostate diffuse optical tomography and spectroscopy: A simulation study. Med Phys 2007;34:266–274.
ROBERT J. SCHULZ, PH.D. Department of Therapeutic Radiology Yale University New Haven, CT A. ROBERT KAGAN, M.D. Department of Radiation Oncology Southern California Permanente Medical Group Los Angeles, CA doi:10.1016/j.ijrobp.2007.08.037 1. Eade TN, Hanlon AL, Horwitz EM, et al. What dose of external-beam radiation is high enough for prostate cancer. Int J Radiat Oncol Biol Phys 2007;68:682–689.
IN REPLY TO DRS. CHEUNG AND SCHULZ AND KAGAN To the Editor: Reply to Dr. Cheung Our data (1) show that a substantial prostate cancer dose–response relationship exists between 76 and 82 Gy. The recommendation to treat to doses of $80 Gy was determined from results from treatment of the entire prostate. The promising concept of dose escalation to a portion of the prostate is not new (2–5); however, little definitive evidence exists on how to best integrate imaging and biopsy information into treatment planning and delivery. Outcome data are lacking. This is an evolving research area that will take 5–10 years to mature once a method has been tested in a Phase III trial. The pertinent question now is the safety of administering doses $80 Gy to the whole prostate. The data from Fox Chase (6, 7), Memorial Sloan-Kettering (8), Cleveland Clinic (9), and other institutions have indicated that the toxicity of doses in this range can be kept relatively low with appropriate constraints. 645
646
I. J. Radiation Oncology d Biology d Physics
Reply to Drs. Schulz and Kagan As noted, an imbalance was present among the dose groups in the Fox Chase cohort (1) in terms of Gleason score .6. However, the dose–response results shown were adjusted for Gleason score, as well as pretreatment initial prostate-specific antigen level and T stage. Concerning the distant metastasis analysis, the dose–response relationship was clearly less conclusive than that for biochemical failure. Far fewer distant metastasis events occurred, limiting the power of the observations. Despite this limitation, and the other potentially confounding factors we describe in the ‘‘Discussion’’ section (1), consistency has been found in the relationship between an increasing radiation dose and reduced distant metastasis from prostate cancer (see Table 4 in Eade et al. [1]) (10, 11). Moreover, the association of biochemical failure to distant metastasis and survival is unquestionably robust (12, 13). The dose– response relation for biochemical failure translates into a dose–response relationship for distant spread, which we anticipate will strengthen with longer follow-up and more events. To achieve long-term freedom from failure, most men will need to be treated with doses of $80 Gy. Rather than scientifically undefined ‘‘social factors’’ dictating the dose prescription, our approach has been to maintain the current levels of toxicity, and possibly reduce them, through strict normal tissue constraints. ALAN POLLACK, M.D., PH.D. Department of Radiation Oncology Fox Chase Cancer Center Philadelphia, PA THOMAS N. EADE, F.R.A.N.Z.C.R. Department of Radiation Oncology Royal North Shore Hospital Sydney, Australia ALEXANDRA L. HANLON, PH.D. Department of Public Health Temple University Philadelphia, PA ERIC M. HORWITZ, M.D. Department of Radiation Oncology Fox Chase Cancer Center Philadelphia, PA MARK K. BUYYOUNOUSKI, M.D. Department of Radiation Oncology Fox Chase Cancer Center Philadelphia, PA GERALD E. HANKS, M.D., F.A.S.T.R.O. Emeritus Department of Radiation Oncology Fox Chase Cancer Center Philadelphia, PA doi:10.1016/j.ijrobp.2007.08.002 1. Eade TN, Hanlon AL, Horwitz EM, et al. What dose of external-beam radiation is high enough for prostate cancer? Int J Radiat Oncol Biol Phys 2007;68:682–689. 2. Pickett B, Vigneault E, Kurhanewicz J, et al. Static field intensity modulation to treat a dominant intra-prostatic lesion to 90 Gy compared to seven field 3-dimensional radiotherapy. Int J Radiat Oncol Biol Phys 1999;44:921–929. 3. Xia P, Pickett B, Vigneault E, et al. Forward or inversely planned segmental multileaf collimator IMRT and sequential tomotherapy to treat multiple dominant intraprostatic lesions of prostate cancer to 90 Gy. Int J Radiat Oncol Biol Phys 2001;51:244–254. 4. Ling CC, Humm J, Larson S, et al. Towards multidimensional radiotherapy (MD-CRT): Biological imaging and biological conformality. Int J Radiat Oncol Biol Phys 2000;47:551–560. 5. van Lin EN, Futterer JJ, Heijmink SW, et al. IMRT boost dose planning on dominant intraprostatic lesions: Gold marker-based three-dimensional fusion of CT with dynamic contrast-enhanced and 1H-spectroscopic MRI. Int J Radiat Oncol Biol Phys 2006;65:291–303. 6. Chism DB, Horwitz EM, Hanlon AL, et al. Late morbidity profiles in prostate cancer patients treated to 79–84 Gy by a simple four-field coplanar beam arrangement. Int J Radiat Oncol Biol Phys 2003;55:71–77. 7. Pollack A, Hanlon AL, Horwitz EM, et al. Dosimetry and preliminary acute toxicity in the first 100 men treated for prostate cancer on a random-
Volume 70, Number 2, 2008
8. 9.
10. 11. 12. 13.
ized hypofractionation dose escalation trial. Int J Radiat Oncol Biol Phys 2006;64:518–526. Zelefsky MJ, Chan H, Hunt M, et al. Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer. J Urol 2006;176:1415–1419. Kupelian PA, Willoughby TR, Reddy CA, et al. Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: Cleveland Clinic experience. Int J Radiat Oncol Biol Phys 2007;68:1424–1430. Jacob R, Hanlon AL, Horwitz EM, et al. The relationship of increasing radiotherapy dose to reduced distant metastases and mortality in men with prostate cancer. Cancer 2004;100:538–543. Morgan PB, Hanlon AL, Horwitz EM, et al. Radiation dose and late failures in prostate cancer. Int J Radiat Oncol Biol Phys 2007;67:1074–1081. Pollack A, Hanlon AL, Movsas B, et al. Biochemical failure as a determinant of distant metastasis and death in prostate cancer treated with radiotherapy. Int J Radiat Oncol Biol Phys 2003;57:19–23. Abramowitz MC, Li T, Buyyounouski MK, et al. The Phoenix definition of biochemical failure predicts for overall survival in patients with prostate cancer. Cancer 2007;112:55–60.
IMAGE-GUIDED RADIATION THERAPY: MANY ROADS LEAD TO ROME? To the Editor: We read with interest the correspondence between Scarbrough et al. (1) and Poli et al. (2) regarding systematic setup errors when using ultrasound-based image guidance. Disregarding the ‘‘tone unusual for scientific discourse’’, we would like to shed some light on the following issues from a different angle. Scarborough et al. recognized correctly that methodical shortcomings are encountered in a plethora of publications regarding ultrasound-based systems. In the past, problems when evaluating these systems’ precision was that either no real-time correlation between ultrasound and a second imaging modality could be achieved (2–4) or that technical issues (deterioration of encoders) were not detected (5). Quality assurance recommendations from the manufacturer of one system were initially insufficient to pick up these spurious errors, which are most likely responsible for some reported systematic errors (6, 7). The authors of these reports investigated this issue, which has meanwhile been completely resolved by using non-encoder-based systems. Other critiques regarding potential target displacement by ultrasound imaging (pressure) suffered from the fact that it was based on work with nondedicated equipment in a nonclinical setting (8). Data acquired in the clinical setting with a dedicated system did not demonstrate these problems (5). It is time to rehabilitate ultrasound-based image guidance. Accuracy of ultrasound-based systems can now be evaluated with fiducial-based simultaneous three-dimensional imaging with kV/MV cone/fan-beam CT. Measurements in Mannheim comparing ultrasound-based image guidance with fiducial-based kV-CBCT have shown a systematic residual error \1.7 mm in each room direction for a group of users with varying educational levels. SD of the systematic errors was \2.3 mm, and SD of the random error was \3 mm in each direction. Calibration allows a precision of #1 mm on the basis of phantom measurements. These values meet the accuracy recommendations of extracranial stereotaxy and are sufficient for narrow-margin precision radiotherapy. Granted, ultrasound as a user-dependent modality should only be used when adequate training has been provided, a requirement that applies to the use of any technology. European curricula have mandated ultrasound training for radiation oncologists, facilitating the introduction of these systems. On the upside, these systems are now technically highly reliable, allow avoiding excess radiation exposure, and are cost-effective. Many roads lead to Rome; similarly, high-quality image guidance can be performed with a host of technical solutions. No system will be free of errors without proper calibration and if it is used without a sound knowledge of anatomy. Thanks to image-guided radiation therapy, we can now assess the location of target volumes. We can choose among several excellent methods: in-room kV/MV volumetric imaging, planar radiographs, beacon responders, ultrasound and, in the future, perhaps MRI as well. Furthermore, because image-guided radiation therapy is such a beautiful procedure, we do not think we should ever have enough! JUDIT BODA-HEGGEMANN, M.D., PH.D. FREDERICK MARC KO¨HLER, M.SC. University of Heidelberg Mannheim, Germany
LETTERS TO THE EDITOR THE NEED AND PROSPECT OF INDIVIDUALIZED EXTERNAL BEAM RADIOTHERAPY DOSE ESCALATION BEYOND 80 GY TO TREAT PROSTATE CANCER: IN REGARD TO EADE ET AL. (INT J RADIAT ONCOL BIOL PHYS 2007;68:682–689)
COMMENTARY ON DOSE ESCALATION AND BIOCHEMICAL FAILURE IN PROSTATE CANCER: IN REGARD TO EADE ET AL. (INT J RADIAT ONCOL BIOL PHYS 2007;68:682–689) To the Editor: Based on a retrospective study, Eade et al. (1) recommend that doses of $80 Gy be administered for the treatment of prostate cancer. The basis for this recommendation was their observation that higher doses reduce the probability of biochemical failure and the incidence of distant metastases. Specifically, the 1,530 men included in their study were divided into four dose groups: \70 Gy, 70–74.9 Gy, 75–79.9 Gy, and $80 Gy. Using the Phoenix criterion, Eade et al. (1) observed that the 5-year freedom from biochemical failure rate for each of the four groups increased as the dose increased: 70%, 81%, 83%, and 89% respectively. All well and good for freedom from biochemical failure; however, when it comes to the proportion of men with freedom from distant metastases at 5 and 10 years, the effect of dose escalation is obscure, with corresponding rates of 96% and 93%, 97% and 93%, 99% and 95%, and 98% and 96%. Given that 55% of the $80-Gy group had Gleason scores .6 and 98%, 80%, and 81% of the lower dose groups had scores in the range of 2–6, it could be that $80 Gy should be given to men with Gleason scores .6. However, the authors’ freedom from distant metastases results for the three lower dose groups were essentially the same, suggesting, if anything, that 70 Gy is sufficient. It seems to us that a patient’s survival, regardless of how defined, provides a better measure of a treatment’s efficacy than the subsequent prostate-specific antigen levels. Because greater doses inevitably increase the probability of gastrointestinal and genitourinary toxicities and 80–85% of prostate cancer patients die of other causes, a balance should be struck between the potential benefits of dose escalation and the patient’s quality of life. The recommendation of Eade et al. ‘‘that the vast majority of patients should receive $80 Gy’’ should be tempered by consideration of the myriad clinical and social factors that are unique to each and every patient.
To the Editor: Data are accumulating, including from the study by Eade et al. (1), that doses .80 Gy might provide additional improvement in treatment outcome for intermediate- and high-risk prostate cancer patients. What is much less clear is whether the entire prostate should receive the additional dose. The rates of rectal and genitourinary side effects associated with prostate cancer external beam radiotherapy are reasonably low at present. However, unless the doses to these normal tissues are maintained near the present level, the risks of rectal and urinary toxicity, albeit mostly low grade, are projected to increase steeply (2, 3). Also, longer term data have shown that the incidence of urinary toxicity, unlike rectal toxicity, continues to increase even after 5 years of follow-up (3, 4). Radiation-induced erectile dysfunction (5, 6) is another severe and common side effect that might limit dose escalation. Thus, treating the entire prostate with a margin .80 Gy might risk increasing normal tissue toxicity. Along this line, the alternative of directing the additional doses only to specific intraprostatic regions is worth considering because this will add smaller doses to the surrounding normal tissues (7). Furthermore, novel imaging techniques might allow us in the future to monitor the physiology of the prostate cancer during a course of radiotherapy (8, 9). Clearly, much more research is needed. This approach, however, holds the promise of individualizing the next phase of prostate cancer external beam dose escalation to only the radiation-resistant areas in the prostate. M. REX CHEUNG, M.D., PH.D. Department of Radiation Oncology University of Texas M.D. Anderson Cancer Center Houston, TX doi:10.1016/j.ijrobp.2007.08.001 1. Eade TN, Hanlon AL, Horwitz EM, et al. What dose of external-beam radiation is high enough for prostate cancer? Int J Radiat Oncol Biol Phys 2007;68:682–689. 2. Tucker SL, Cheung R, Dong L, et al. Dose–volume response analyses of late rectal bleeding after radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2004;59:353–365. 3. Cheung MR, Tucker SL, Dong L. Investigation of bladder dose and volume factors influencing late urinary toxicity after external beam radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2007;67: 1059–1065. 4. Gardner BG, Zietman AL, Shipley WU, et al. Late normal tissue sequelae in the second decade after high dose radiation therapy with combined photons and conformal protons for locally advanced prostate cancer. J Urol 2002;167:123–126. 5. Selek U, Cheung R, Lii M, et al. Erectile dysfunction and radiation dose to penile base structures: A lack of correlation. Int J Radiat Oncol Biol Phys 2004;59:1039–1046. 6. Roach M, Winter K, Michalski JM, et al. Penile bulb dose and impotence after three-dimensional conformal radiotherapy for prostate cancer on RTOG 9406: Findings from a prospective, multi-institutional, phase I/II dose-escalation study. Int J Radiat Oncol Biol Phys 2004;60: 1351–1356. 7. van Lin EN, Futterer JJ, Heijmink SW, et al. IMRT boost dose planning on dominant intraprostatic lesions: Gold marker-based three-dimensional fusion of CT with dynamic contrast-enhanced and 1H-spectroscopic MRI. Int J Radiat Oncol Biol Phys 2006;65:291–303. 8. Pickett B, Kurhanewicz J, Coakley F, et al. Use of MRI and spectroscopy in evaluation of external beam radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2004;60:1047–1055. 9. Li C, Liengsawangwong R, Choi H, et al. Using a priori structural information from magnetic resonance imaging to investigate the feasibility of prostate diffuse optical tomography and spectroscopy: A simulation study. Med Phys 2007;34:266–274.
ROBERT J. SCHULZ, PH.D. Department of Therapeutic Radiology Yale University New Haven, CT A. ROBERT KAGAN, M.D. Department of Radiation Oncology Southern California Permanente Medical Group Los Angeles, CA doi:10.1016/j.ijrobp.2007.08.037 1. Eade TN, Hanlon AL, Horwitz EM, et al. What dose of external-beam radiation is high enough for prostate cancer. Int J Radiat Oncol Biol Phys 2007;68:682–689.
IN REPLY TO DRS. CHEUNG AND SCHULZ AND KAGAN To the Editor: Reply to Dr. Cheung Our data (1) show that a substantial prostate cancer dose–response relationship exists between 76 and 82 Gy. The recommendation to treat to doses of $80 Gy was determined from results from treatment of the entire prostate. The promising concept of dose escalation to a portion of the prostate is not new (2–5); however, little definitive evidence exists on how to best integrate imaging and biopsy information into treatment planning and delivery. Outcome data are lacking. This is an evolving research area that will take 5–10 years to mature once a method has been tested in a Phase III trial. The pertinent question now is the safety of administering doses $80 Gy to the whole prostate. The data from Fox Chase (6, 7), Memorial Sloan-Kettering (8), Cleveland Clinic (9), and other institutions have indicated that the toxicity of doses in this range can be kept relatively low with appropriate constraints. 645
646
I. J. Radiation Oncology d Biology d Physics
Reply to Drs. Schulz and Kagan As noted, an imbalance was present among the dose groups in the Fox Chase cohort (1) in terms of Gleason score .6. However, the dose–response results shown were adjusted for Gleason score, as well as pretreatment initial prostate-specific antigen level and T stage. Concerning the distant metastasis analysis, the dose–response relationship was clearly less conclusive than that for biochemical failure. Far fewer distant metastasis events occurred, limiting the power of the observations. Despite this limitation, and the other potentially confounding factors we describe in the ‘‘Discussion’’ section (1), consistency has been found in the relationship between an increasing radiation dose and reduced distant metastasis from prostate cancer (see Table 4 in Eade et al. [1]) (10, 11). Moreover, the association of biochemical failure to distant metastasis and survival is unquestionably robust (12, 13). The dose– response relation for biochemical failure translates into a dose–response relationship for distant spread, which we anticipate will strengthen with longer follow-up and more events. To achieve long-term freedom from failure, most men will need to be treated with doses of $80 Gy. Rather than scientifically undefined ‘‘social factors’’ dictating the dose prescription, our approach has been to maintain the current levels of toxicity, and possibly reduce them, through strict normal tissue constraints. ALAN POLLACK, M.D., PH.D. Department of Radiation Oncology Fox Chase Cancer Center Philadelphia, PA THOMAS N. EADE, F.R.A.N.Z.C.R. Department of Radiation Oncology Royal North Shore Hospital Sydney, Australia ALEXANDRA L. HANLON, PH.D. Department of Public Health Temple University Philadelphia, PA ERIC M. HORWITZ, M.D. Department of Radiation Oncology Fox Chase Cancer Center Philadelphia, PA MARK K. BUYYOUNOUSKI, M.D. Department of Radiation Oncology Fox Chase Cancer Center Philadelphia, PA GERALD E. HANKS, M.D., F.A.S.T.R.O. Emeritus Department of Radiation Oncology Fox Chase Cancer Center Philadelphia, PA doi:10.1016/j.ijrobp.2007.08.002 1. Eade TN, Hanlon AL, Horwitz EM, et al. What dose of external-beam radiation is high enough for prostate cancer? Int J Radiat Oncol Biol Phys 2007;68:682–689. 2. Pickett B, Vigneault E, Kurhanewicz J, et al. Static field intensity modulation to treat a dominant intra-prostatic lesion to 90 Gy compared to seven field 3-dimensional radiotherapy. Int J Radiat Oncol Biol Phys 1999;44:921–929. 3. Xia P, Pickett B, Vigneault E, et al. Forward or inversely planned segmental multileaf collimator IMRT and sequential tomotherapy to treat multiple dominant intraprostatic lesions of prostate cancer to 90 Gy. Int J Radiat Oncol Biol Phys 2001;51:244–254. 4. Ling CC, Humm J, Larson S, et al. Towards multidimensional radiotherapy (MD-CRT): Biological imaging and biological conformality. Int J Radiat Oncol Biol Phys 2000;47:551–560. 5. van Lin EN, Futterer JJ, Heijmink SW, et al. IMRT boost dose planning on dominant intraprostatic lesions: Gold marker-based three-dimensional fusion of CT with dynamic contrast-enhanced and 1H-spectroscopic MRI. Int J Radiat Oncol Biol Phys 2006;65:291–303. 6. Chism DB, Horwitz EM, Hanlon AL, et al. Late morbidity profiles in prostate cancer patients treated to 79–84 Gy by a simple four-field coplanar beam arrangement. Int J Radiat Oncol Biol Phys 2003;55:71–77. 7. Pollack A, Hanlon AL, Horwitz EM, et al. Dosimetry and preliminary acute toxicity in the first 100 men treated for prostate cancer on a random-
Volume 70, Number 2, 2008
8. 9.
10. 11. 12. 13.
ized hypofractionation dose escalation trial. Int J Radiat Oncol Biol Phys 2006;64:518–526. Zelefsky MJ, Chan H, Hunt M, et al. Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer. J Urol 2006;176:1415–1419. Kupelian PA, Willoughby TR, Reddy CA, et al. Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: Cleveland Clinic experience. Int J Radiat Oncol Biol Phys 2007;68:1424–1430. Jacob R, Hanlon AL, Horwitz EM, et al. The relationship of increasing radiotherapy dose to reduced distant metastases and mortality in men with prostate cancer. Cancer 2004;100:538–543. Morgan PB, Hanlon AL, Horwitz EM, et al. Radiation dose and late failures in prostate cancer. Int J Radiat Oncol Biol Phys 2007;67:1074–1081. Pollack A, Hanlon AL, Movsas B, et al. Biochemical failure as a determinant of distant metastasis and death in prostate cancer treated with radiotherapy. Int J Radiat Oncol Biol Phys 2003;57:19–23. Abramowitz MC, Li T, Buyyounouski MK, et al. The Phoenix definition of biochemical failure predicts for overall survival in patients with prostate cancer. Cancer 2007;112:55–60.
IMAGE-GUIDED RADIATION THERAPY: MANY ROADS LEAD TO ROME? To the Editor: We read with interest the correspondence between Scarbrough et al. (1) and Poli et al. (2) regarding systematic setup errors when using ultrasound-based image guidance. Disregarding the ‘‘tone unusual for scientific discourse’’, we would like to shed some light on the following issues from a different angle. Scarborough et al. recognized correctly that methodical shortcomings are encountered in a plethora of publications regarding ultrasound-based systems. In the past, problems when evaluating these systems’ precision was that either no real-time correlation between ultrasound and a second imaging modality could be achieved (2–4) or that technical issues (deterioration of encoders) were not detected (5). Quality assurance recommendations from the manufacturer of one system were initially insufficient to pick up these spurious errors, which are most likely responsible for some reported systematic errors (6, 7). The authors of these reports investigated this issue, which has meanwhile been completely resolved by using non-encoder-based systems. Other critiques regarding potential target displacement by ultrasound imaging (pressure) suffered from the fact that it was based on work with nondedicated equipment in a nonclinical setting (8). Data acquired in the clinical setting with a dedicated system did not demonstrate these problems (5). It is time to rehabilitate ultrasound-based image guidance. Accuracy of ultrasound-based systems can now be evaluated with fiducial-based simultaneous three-dimensional imaging with kV/MV cone/fan-beam CT. Measurements in Mannheim comparing ultrasound-based image guidance with fiducial-based kV-CBCT have shown a systematic residual error \1.7 mm in each room direction for a group of users with varying educational levels. SD of the systematic errors was \2.3 mm, and SD of the random error was \3 mm in each direction. Calibration allows a precision of #1 mm on the basis of phantom measurements. These values meet the accuracy recommendations of extracranial stereotaxy and are sufficient for narrow-margin precision radiotherapy. Granted, ultrasound as a user-dependent modality should only be used when adequate training has been provided, a requirement that applies to the use of any technology. European curricula have mandated ultrasound training for radiation oncologists, facilitating the introduction of these systems. On the upside, these systems are now technically highly reliable, allow avoiding excess radiation exposure, and are cost-effective. Many roads lead to Rome; similarly, high-quality image guidance can be performed with a host of technical solutions. No system will be free of errors without proper calibration and if it is used without a sound knowledge of anatomy. Thanks to image-guided radiation therapy, we can now assess the location of target volumes. We can choose among several excellent methods: in-room kV/MV volumetric imaging, planar radiographs, beacon responders, ultrasound and, in the future, perhaps MRI as well. Furthermore, because image-guided radiation therapy is such a beautiful procedure, we do not think we should ever have enough! JUDIT BODA-HEGGEMANN, M.D., PH.D. FREDERICK MARC KO¨HLER, M.SC. University of Heidelberg Mannheim, Germany