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Second Malignancies After Radiotherapy for Prostate Cancer: Keeping Perspective
Point-CounterPoint Second Malignancies After Radiotherapy for Prostate Cancer: Keeping Perspective The history of radiotherapy (RT) in the treatment of prostate cancer dates back to 1911 with the first use of radium-based intraprostatic brachytherapy.1 The success of RT as a highly curative modality for localized prostate cancer is well established.2 Nevertheless, prostatic irradiation has been beleaguered by inconsistent reports of radiation-induced malignancies. Although the role of ionizing radiation in carcinogenesis has been duly recognized, we hope that properly framing the existing data will provide a clearer perspective of its acceptable absolute risks. The editorial by Herr and Carver relies heavily on several studies that used the Surveillance, Epidemiology, and End Results (SEER) database, which has furnished most of the publications demonstrating significant risks of radiation-induced malignancies. However, even the SEER publications have had conflicting results and are susceptible to the dangers of selection bias. Criticisms of the SEER analyses include incomplete patient information as a tradeoff for larger patient numbers, crude source documentation, use of antiquated radiation techniques that often delivered lower energy photons to larger fields, and failure to account for differences in follow-up patterns between urologists and radiation oncologists. Their editorial focuses on the 2 SEER analyses that reported positive findings.3,4 However, at least 3 other SEERbased publications5-8 have reported mixed results. The strongest counterargument to Herr and Carver is made in the update by Kendal et al.,6 which included ⬎500 000 cases of prostate cancer in a model that was adjusted for age and follow-up interval and found no increased risks of second malignancy at any site. Herr and Carver have based their calculations on data from Brenner et al.,3 a SEER analysis that compared men with prostate cancer treated with RT vs surgery without RT and reported the second malignancy risks listed in their editorial’s Table 1. Although a SEER analysis should be applauded for the potential of large populations to increase the statistical power, 86% of the patients were followed up for 1-5 years after diagnosis, an interval far too brief to make conclusions about the development of radiation-induced malignancies.9 Surprisingly, the rates Reprint requests: Howard M. Sandler, M.D., M.S., Department of Radiation Oncology, University of Michigan Medical School, UH B2C490, Box 0010, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0010. E-mail: [email protected] Submitted: July 7, 2008, accepted (with revisions): July 10, 2008
© 2008 Elsevier Inc. All Rights Reserved
of second malignancy in both the RT and the surgical groups were actually less than what would be expected of the general population, casting doubt on the applicability of the data to real life. Perhaps the more relevant analysis of Brenner et al.3 was an estimation of the absolute numbers of second solid tumors attributable to RT— only 1 per 1220 person-years in total. The largest weakness of all SEER analyses is the failure to capture information on tobacco use and include it as a covariate in their models. It is reasonable to believe that a selection bias toward nonsmokers exists for prostatectomy compared with RT. Brenner et al.3 found that the small increases in relative risk for secondary solid tumors (6%) were primarily driven by lung and bladder cancers that occurred within 5 years. This clinical scenario has stronger ties to smoking than RT. Similarly, the inability to adjust for this confounder led Moon et al.4 to conclude that “differences in the occurrence of secondary cancers observed in this study may reflect in part differences among patients in their indications for treatment, smoking history, or in other confounders that were not included in the multivariate adjustments.” One single-institution trial did record lifestyle variables and reported that 82% of irradiated patients with second primaries had a history of tobacco and/or alcohol use and 97% of the second cancers occurred within 3 years of RT.10 The editorial by Herr and Carver disregards the results of several large, single-institution and tumor registry studies that found no increases in bladder10-14 or colorectal cancer10,12 after prostatic irradiation. One such study actually demonstrated a decrease in the rate of bladder and testicular cancer in the RT compared with the non-RT group, suggesting that the effect of confounding factors has been greatly underappreciated in all such analyses.14 Even though several of these studies included thousands of patients, they have still been criticized for their inability to detect differences in second malignancies after irradiation. In contrast, the need for extraordinary statistical power should underscore the clinical insignificance of any risks. Overall survival remains the most significant endpoint for cancer patients. The declaration in the editorial by Herr and Carver that radiation-induced malignancies cause more deaths than prostate cancer itself is precarious at best, because their core assumptions are faulty. First, it would be more relevant to estimate survival detriments
UROLOGY 72: 971–973, 2008 • 0090-4295/08/$34.00 doi:10.1016/j.urology.2008.07.016
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using the “excess risk” rather than the “absolute risk” of malignancy after RT (5%), because most of these are attributable to background cases that would occur without RT (3.7%). Second, they assumed that each second malignancy would be universally fatal, even though no data are available to support this claim. A recent publication reviewed the outcomes of bladder cancers that occurred after prostatic irradiation and concluded that survival was no different from that in an unirradiated control group.15 Third, a reasonable comparison of treatment-related mortality must include the perioperative mortality rate after radical prostatectomy, which has been consistently reported as 0.5% at 30 days after surgery.16-18 In a SEER analysis of nearly 12 000 men, Begg et al.16 reported that the 30-day prostatectomy mortality rate of 0.5% remained unchanged across all quartiles of hospital and surgeon volume. Let us assume that 100 men with prostate cancer have chosen to undergo radical prostatectomy. According to the most recent U.S. Life Tables,19 a 70-year-old man (mean age in the study by Brenner et al.3) is expected to live an additional 14 years. If the 30-day perioperative mortality rate is 0.5%, it can be concluded that the risk of prostatectomy would lead to the loss of 7 person-years. If the same 100 men chose RT, we might expect an excess of 1.3% second malignancies. Presuming that these radiation-induced malignancies occur early (within 5 years) and are immediately fatal in 60% of the men, this would also lead to a loss of 7 person-years. Although this is an oversimplification of how radiation-induced malignancies originate and progress, it is clear that treatment-related mortalities from prostatectomy and RT must be compared fairly. As technology advances in RT, so does the concern that intensity-modulated RT will increase the rates of second malignancies.20 Although this theoretical concern exists, estimates have generally been based on a model derived from the survivors of the atomic bomb attack on Japan. Because these data are only directly applicable to exposures of high radiation doses at high rates, most estimates require a correction factor, the true value of which is unknown. Although intensity-modulated RT is associated with an increased beam-on time and leakage of dose through the leaves of the multileaf collimator, the ability to treat smaller volumes has reduced the amount of scatter radiation, which is the main contributor to the dose within 14 cm of the field.21 Because intensity-modulated RT is an emerging technology, quantifying its effect on the development of second malignancies will require the collection of clinical data for decades. Both RT and prostatectomy offer high rates of cure for men with localized prostate cancer. This success gives patients the freedom to make treatment decisions on the basis of convenience, morbidity profiles, and personal preference. A recent prospective quality-of-life study detected significant declines in sexual scores after prosta972
tectomy compared with pretreatment baseline levels. However, no significant declines were noted in those treated with external beam RT in the absence of neoadjuvant hormonal therapy.22 The converse phenomenon was demonstrated for bowel/rectal scores. Clearly, the choice for RT vs prostatectomy in the treatment of prostate cancer is not absolute but is instead a personal decision. In this light, we hope that a healthy perspective will allow urologists and radiation oncologists to continue working together for the best interests of men with prostate cancer. Kevin S. Oh and Howard M. Sandler From the Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan
References 1. Pasteau O. Traitment du cancer de la prostate par le radium. Rev Mal Nutr. 1911;363-367. 2. D’Amico AV, Moul J, Carroll PR, et al. Cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. J Clin Oncol. 2003;21:2163-2172. 3. Brenner DJ, Curtis RE, Hall EJ, et al. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer. 2000;88:398-406. 4. Moon K, Stukenborg GJ, Keim J, et al. Cancer incidence after localized therapy for prostate cancer. Cancer. 2006;107:991-998. 5. Baxter NN, Tepper JE, Durham SB, et al. Increased risk of rectal cancer after prostate radiation: A population-based study. Gastroenterology. 2005;128:819-824. 6. Kendal W, Eapen L, Nicholas G. Second primary cancers after prostatic irradiation: Ensuring an appropriate analysis. Cancer. 2007;109:165. 7. Neugut AI, Ahsan H, Robinson E, et al. Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma. Cancer. 1997;79:1600-1604. 8. Kendal WS, Eapen L, Macrae R, et al. Prostatic irradiation is not associated with any measurable increase in the risk of subsequent rectal cancer. Int J Radiat Oncol Biol Phys. 2006;65:661-668. 9. Jao SW, Beart RW Jr, Reiman HM, et al. Colon and anorectal cancer after pelvic irradiation. Dis Colon Rectum. 1987;30:953-958. 10. Movsas B, Hanlon AL, Pinover W, et al. Is there an increased risk of second primaries following prostate irradiation? Int J Radiat Oncol Biol Phys. 1998;41:251-255. 11. Chrouser K, Leibovich B, Bergstralh E, et al. Bladder cancer risk following primary and adjuvant external beam radiation for prostate cancer. J Urol. 2005;174:107-111. 12. Mikata N, Imao S, Fukasawa R. [Second cancer after starting treatment for prostate cancer]. Gan To Kagaku Ryoho. 2002;29: 1411-1415. 13. Pawlish KS, Schottenfeld D, Severson R, et al. Risk of multiple primary cancers in prostate cancer patients in the Detroit metropolitan area: A retrospective cohort study. Prostate. 1997;33:75-86. 14. Pickles T, Phillips N. The risk of second malignancy in men with prostate cancer treated with or without radiation in British Columbia, 1984-2000. Radiother Oncol. 2002;65:145-151. 15. Sandhu JS, Vickers AJ, Bochner B, et al. Clinical characteristics of bladder cancer in patients previously treated with radiation for prostate cancer. BJU Int. 2006;98:59-62. 16. Begg CB, Riedel ER, Bach PB, et al. Variations in morbidity after radical prostatectomy. N Engl J Med. 2002;346:1138-1144.
UROLOGY 72 (5), 2008
17. Karakiewicz PI, Bazinet M, Aprikian AG, et al. Thirty-day mortality rates and cumulative survival after radical retropubic prostatectomy. Urology. 1998;52:1041-1046. 18. Yao SL, Lu-Yao G. Population-based study of relationships between hospital volume of prostatectomies, patient outcomes, and length of hospital stay. J Natl Cancer Inst. 1999;91:1950-1956. 19. Arias E. United States life tables, 2004. Natl Vital Stat Rep. 2007; 56:1-39.
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20. Hall EJ, Wuu CS. Radiation-induced second cancers: The impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys. 2003; 56:83-88. 21. Lillicrap SC, Morgan HM, Shakeshaft JT. X-ray leakage during radiotherapy. Br J Radiol. 2000;73:793-794. 22. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med. 2008;358:1250-1261.
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© 2008 Elsevier Inc. All Rights Reserved
of second malignancy in both the RT and the surgical groups were actually less than what would be expected of the general population, casting doubt on the applicability of the data to real life. Perhaps the more relevant analysis of Brenner et al.3 was an estimation of the absolute numbers of second solid tumors attributable to RT— only 1 per 1220 person-years in total. The largest weakness of all SEER analyses is the failure to capture information on tobacco use and include it as a covariate in their models. It is reasonable to believe that a selection bias toward nonsmokers exists for prostatectomy compared with RT. Brenner et al.3 found that the small increases in relative risk for secondary solid tumors (6%) were primarily driven by lung and bladder cancers that occurred within 5 years. This clinical scenario has stronger ties to smoking than RT. Similarly, the inability to adjust for this confounder led Moon et al.4 to conclude that “differences in the occurrence of secondary cancers observed in this study may reflect in part differences among patients in their indications for treatment, smoking history, or in other confounders that were not included in the multivariate adjustments.” One single-institution trial did record lifestyle variables and reported that 82% of irradiated patients with second primaries had a history of tobacco and/or alcohol use and 97% of the second cancers occurred within 3 years of RT.10 The editorial by Herr and Carver disregards the results of several large, single-institution and tumor registry studies that found no increases in bladder10-14 or colorectal cancer10,12 after prostatic irradiation. One such study actually demonstrated a decrease in the rate of bladder and testicular cancer in the RT compared with the non-RT group, suggesting that the effect of confounding factors has been greatly underappreciated in all such analyses.14 Even though several of these studies included thousands of patients, they have still been criticized for their inability to detect differences in second malignancies after irradiation. In contrast, the need for extraordinary statistical power should underscore the clinical insignificance of any risks. Overall survival remains the most significant endpoint for cancer patients. The declaration in the editorial by Herr and Carver that radiation-induced malignancies cause more deaths than prostate cancer itself is precarious at best, because their core assumptions are faulty. First, it would be more relevant to estimate survival detriments
UROLOGY 72: 971–973, 2008 • 0090-4295/08/$34.00 doi:10.1016/j.urology.2008.07.016
971
using the “excess risk” rather than the “absolute risk” of malignancy after RT (5%), because most of these are attributable to background cases that would occur without RT (3.7%). Second, they assumed that each second malignancy would be universally fatal, even though no data are available to support this claim. A recent publication reviewed the outcomes of bladder cancers that occurred after prostatic irradiation and concluded that survival was no different from that in an unirradiated control group.15 Third, a reasonable comparison of treatment-related mortality must include the perioperative mortality rate after radical prostatectomy, which has been consistently reported as 0.5% at 30 days after surgery.16-18 In a SEER analysis of nearly 12 000 men, Begg et al.16 reported that the 30-day prostatectomy mortality rate of 0.5% remained unchanged across all quartiles of hospital and surgeon volume. Let us assume that 100 men with prostate cancer have chosen to undergo radical prostatectomy. According to the most recent U.S. Life Tables,19 a 70-year-old man (mean age in the study by Brenner et al.3) is expected to live an additional 14 years. If the 30-day perioperative mortality rate is 0.5%, it can be concluded that the risk of prostatectomy would lead to the loss of 7 person-years. If the same 100 men chose RT, we might expect an excess of 1.3% second malignancies. Presuming that these radiation-induced malignancies occur early (within 5 years) and are immediately fatal in 60% of the men, this would also lead to a loss of 7 person-years. Although this is an oversimplification of how radiation-induced malignancies originate and progress, it is clear that treatment-related mortalities from prostatectomy and RT must be compared fairly. As technology advances in RT, so does the concern that intensity-modulated RT will increase the rates of second malignancies.20 Although this theoretical concern exists, estimates have generally been based on a model derived from the survivors of the atomic bomb attack on Japan. Because these data are only directly applicable to exposures of high radiation doses at high rates, most estimates require a correction factor, the true value of which is unknown. Although intensity-modulated RT is associated with an increased beam-on time and leakage of dose through the leaves of the multileaf collimator, the ability to treat smaller volumes has reduced the amount of scatter radiation, which is the main contributor to the dose within 14 cm of the field.21 Because intensity-modulated RT is an emerging technology, quantifying its effect on the development of second malignancies will require the collection of clinical data for decades. Both RT and prostatectomy offer high rates of cure for men with localized prostate cancer. This success gives patients the freedom to make treatment decisions on the basis of convenience, morbidity profiles, and personal preference. A recent prospective quality-of-life study detected significant declines in sexual scores after prosta972
tectomy compared with pretreatment baseline levels. However, no significant declines were noted in those treated with external beam RT in the absence of neoadjuvant hormonal therapy.22 The converse phenomenon was demonstrated for bowel/rectal scores. Clearly, the choice for RT vs prostatectomy in the treatment of prostate cancer is not absolute but is instead a personal decision. In this light, we hope that a healthy perspective will allow urologists and radiation oncologists to continue working together for the best interests of men with prostate cancer. Kevin S. Oh and Howard M. Sandler From the Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan
References 1. Pasteau O. Traitment du cancer de la prostate par le radium. Rev Mal Nutr. 1911;363-367. 2. D’Amico AV, Moul J, Carroll PR, et al. Cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. J Clin Oncol. 2003;21:2163-2172. 3. Brenner DJ, Curtis RE, Hall EJ, et al. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer. 2000;88:398-406. 4. Moon K, Stukenborg GJ, Keim J, et al. Cancer incidence after localized therapy for prostate cancer. Cancer. 2006;107:991-998. 5. Baxter NN, Tepper JE, Durham SB, et al. Increased risk of rectal cancer after prostate radiation: A population-based study. Gastroenterology. 2005;128:819-824. 6. Kendal W, Eapen L, Nicholas G. Second primary cancers after prostatic irradiation: Ensuring an appropriate analysis. Cancer. 2007;109:165. 7. Neugut AI, Ahsan H, Robinson E, et al. Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma. Cancer. 1997;79:1600-1604. 8. Kendal WS, Eapen L, Macrae R, et al. Prostatic irradiation is not associated with any measurable increase in the risk of subsequent rectal cancer. Int J Radiat Oncol Biol Phys. 2006;65:661-668. 9. Jao SW, Beart RW Jr, Reiman HM, et al. Colon and anorectal cancer after pelvic irradiation. Dis Colon Rectum. 1987;30:953-958. 10. Movsas B, Hanlon AL, Pinover W, et al. Is there an increased risk of second primaries following prostate irradiation? Int J Radiat Oncol Biol Phys. 1998;41:251-255. 11. Chrouser K, Leibovich B, Bergstralh E, et al. Bladder cancer risk following primary and adjuvant external beam radiation for prostate cancer. J Urol. 2005;174:107-111. 12. Mikata N, Imao S, Fukasawa R. [Second cancer after starting treatment for prostate cancer]. Gan To Kagaku Ryoho. 2002;29: 1411-1415. 13. Pawlish KS, Schottenfeld D, Severson R, et al. Risk of multiple primary cancers in prostate cancer patients in the Detroit metropolitan area: A retrospective cohort study. Prostate. 1997;33:75-86. 14. Pickles T, Phillips N. The risk of second malignancy in men with prostate cancer treated with or without radiation in British Columbia, 1984-2000. Radiother Oncol. 2002;65:145-151. 15. Sandhu JS, Vickers AJ, Bochner B, et al. Clinical characteristics of bladder cancer in patients previously treated with radiation for prostate cancer. BJU Int. 2006;98:59-62. 16. Begg CB, Riedel ER, Bach PB, et al. Variations in morbidity after radical prostatectomy. N Engl J Med. 2002;346:1138-1144.
UROLOGY 72 (5), 2008
17. Karakiewicz PI, Bazinet M, Aprikian AG, et al. Thirty-day mortality rates and cumulative survival after radical retropubic prostatectomy. Urology. 1998;52:1041-1046. 18. Yao SL, Lu-Yao G. Population-based study of relationships between hospital volume of prostatectomies, patient outcomes, and length of hospital stay. J Natl Cancer Inst. 1999;91:1950-1956. 19. Arias E. United States life tables, 2004. Natl Vital Stat Rep. 2007; 56:1-39.
UROLOGY 72 (5), 2008
20. Hall EJ, Wuu CS. Radiation-induced second cancers: The impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys. 2003; 56:83-88. 21. Lillicrap SC, Morgan HM, Shakeshaft JT. X-ray leakage during radiotherapy. Br J Radiol. 2000;73:793-794. 22. Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med. 2008;358:1250-1261.
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