Opposing Views
Radiation for Prostate Cancer: Intensity Modulated Radiation Therapy versus Proton Beam PROTON BEAM Proton therapy for the management of prostate cancer has been highly scrutinized because of its higher cost compared to photon based radiation therapies like intensity modulated radiation therapy (IMRT). The debate focuses on whether the benefits of proton therapy are worth the higher costs. If patients are treated with the same planning target volume margins, total dose (76 to 80 Gy) and target coverage, then proton therapy allows for a reduction in the radiation dose to the surrounding normal pelvic tissues in the low to moderate dose range of 0 to 50 Gy range compared to IMRT, while maintaining similar volumes of the organs at risk which receive higher doses (60 to 80 Gy).1 Consequently, the greatest advantage of proton therapy is in reducing the risk of side effects that may develop after exposure to 0 to 50 Gy radiation. Furthermore, this advantage might be magnified with the use of hypofractionated treatment. Unrealistic Expectations Rectal bleeding is the most common rectal toxicity, and the risk correlates with blood thinner use and volume of the rectum receiving 70e75 Gy.2 Importantly, proton therapy is not expected to lower the risk of rectal bleeding because it does not reduce the volume of the rectum receiving high doses of radiation compared with IMRT. Similarly, urinary toxicities like urethritis, urethral strictures and cystitis generally occur because of exposure of the urethra and/or bladder neck to high doses of radiation,3 and are not expected to be improved with proton therapy. Studies by Yu4 and Sheets5 et al confirmed these unrealistic expectations. These authors used the SEER (Surveillance, Epidemiology, and End Results)-Medicare database to compare IMRT with proton therapy in patients with prostate cancer and to evaluate toxicity based on ICD-9 codes. Interestingly, the ICD-9 codes they evaluated, such as rectal hemorrhage, ulcers and fistulas, were generally those that occur with high doses of radiation. Considering that patients receiving proton therapy were more likely to be on dose escalated clinical 0022-5347/15/1934-1089/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
trials, it is not surprising the investigators found no benefit and possibly worse toxicity with proton therapy, owing to a higher overall dose prescription among proton patients. Realistic Expectations Exposure of the organs at risk in the pelvis to 0 to 50 Gy radiation may lead to bowel urgency, bowel frequency, erectile dysfunction and secondary cancers.6 Resnick and Penson reported the 15-year functional outcomes after radiation therapy for localized prostate cancer and found that 16% of patients complained of moderate to severe issues with bowel frequency, bowel urgency and/or bowel pain.7 Unlike rectal bleeding, rectal urgency and frequency are generally problems that do not improve over time with further healing and may even worsen. Furthermore, urgency and incontinence were the bowel issues most highly associated with worse overall quality of life for patients irradiated for prostate cancer.8 Unfortunately, a major weakness of the SEER database studies comparing proton therapy and IMRT for prostate cancer is that they did not explore any differences in rectal urgency even though it has an ICD-9 code of 787.63.4 In comparison, in a study of 1,447 men treated with proton therapy or IMRT 15% treated with IMRT complained of moderate or severe problems with bowel urgency, as defined by the EPIC (Expanded Prostate Cancer Index Composite) questionnaire compared to 7% of men treated with proton therapy. Similarly, 10% of men treated with photon radiation complained of EPIC defined bowel frequency compared to 4% treated with proton therapy.9 These differences are statistically significant, clinically relevant and what we would expect based on the reduced volume of rectum receiving 0 to 50 Gy with proton therapy compared to IMRT. A reduced risk for secondary cancers is another potential advantage of proton therapy over photon radiation, particularly for younger men seeking an alternative to surgery. In a cohort study that included 33% of men treated for prostate cancer http://dx.doi.org/10.1016/j.juro.2015.01.069 Vol. 193, 1089-1091, April 2015 Printed in U.S.A.
www.jurology.com
j
1089
1090
OPPOSING VIEWS
proton therapy led to a 50% reduction in secondary cancers compared to photon based radiation.10 Sexual dysfunction is also an important side effect of radiation therapy which can be associated with low testosterone as a result of low photon scatter dose to the testis.11 In contrast, no significant decrease in median testosterone has been reported following proton therapy because it delivers little scatter radiation to the testicles.12 This difference may lead to improvement in sexual function in patients treated with proton therapy. In summary, while we should not overestimate the benefits of proton therapy, we should appreciate proton therapy for what we know it can do, which is significantly reduce the low to moderate doses of excess radiation delivered to organs at risk in the pelvis. This reduction in dose can lead to meaningful risk reductions in bowel urgency, bowel frequency, sexual dysfunction and secondary cancers compared with IMRT. Bradford S. Hoppe and Curtis Bryant University of Florida Proton Therapy Institute Jacksonville, Florida
IMRT Radiation therapy is a treatment modality that is widely acknowledged as effective in the management of prostate cancer.13 It is commonly and beneficially used against prostate cancer in the definitive setting (with the prostate in place) and in the adjuvant or salvage setting following radical prostatectomy. In the management of prostate cancer radiation therapy can be delivered with many different techniques, including photon external beam alone, 3-dimensional conformal therapy, proton beam, external beam in combination with brachytherapy (with either permanent radioactive seeds or high dose rate temporary) or brachytherapy alone. Each of these techniques can, when indicated, be combined with either short-term or long-term androgen deprivation. The potential combinations of modalities are great. However, there is a shortage of high quality comparative clinical trials, and so comparative assessment is often based on series from single institutions, often from experts in one area making valid comparisons challenging and raising questions about generalizability. The radiation oncology community would likely agree on the following 2 points. First, there is no inherent biological basis to expect that 1 Gy photon radiation is less effective than a comparable adjusted Gy of proton therapy. In fact, the dose delivered with proton therapy is carefully adjusted to make it equally tumoricidal compared to photon radiation so that 78 Gy photons (a typical dose for
prostate cancer) is equi-effective vs 78 Gy proton therapy. Second, there is agreement that 78 Gy is an effective treatment for most prostate cancer, regardless of whether proton therapy or IMRT with photons is used, ie there are no major claims that proton therapy at contemporary high doses are better at curing prostate cancer than IMRT when the same doses are used. In essence, the similarities between the 2 approaches are much greater than the putative differences. IMRT is well tolerated and has little adverse impact on patient reported quality of life among all of the relevant domains (bowel, bladder, sexual).14 If there are no known or claimed differences in tumor control between IMRT and proton therapy, are there differences in tolerability and posttreatment morbidity that would favor proton therapy? The radiation oncology community is sensitive to issues regarding post-radiotherapy morbidity, and a meaningful difference in quality of life outcomes favoring proton therapy would be a huge motivating factor towards wider adoption of proton therapy for prostate cancer. To date, based on recent crossinstitutional studies, one would need to conclude that such beneficial differences favoring proton beam do not exist. For example, in the SEER database study of IMRT and proton therapy, IMRT had a lower rate of gastrointestinal morbidity.5 Another study looking at Medicare beneficiaries revealed that there was no difference 12 months after treatment between IMRT and proton therapy for either gastrointestinal or genitourinary toxicity, while proton therapy cost Medicare nearly twice as much per patient treated.4 Finally, in a relatively small comparison study but one that had prospectively collected quality of life information, few differences were seen in quality of life regardless of what modality was used.15 Based upon these recent quality of life studies, one would not be able to conclude that proton therapy is superior to IMRT. Given the level of interest in the use of proton beam for prostate cancer, the existing data suggest that the hypothesis, proton therapy is superior to IMRT, is worth testing prospectively. In fact, there is an ongoing, National Cancer Institute funded, randomized, phase III trial of IMRT vs proton therapy for low and lowintermediate risk prostate cancer (NCT01617161). Since relatively early posttreatment quality of life is the primary end point of the study, outcomes should be available quickly following the accrual of subjects. In 2015 proton therapy is a more expensive modality than IMRT for prostate cancer. If proton treatment is no more effective than IMRT, then it is not cost-effective for prostate cancer. The incremental cost ratio equals the net cost/net benefit. If today there is a net cost for proton therapy above IMRT (and there is) and if the net benefit approaches
OPPOSING VIEWS
zero (as it may), then the incremental cost ratio for proton therapy approaches infinity and argues against widespread adoption of proton therapy for prostate cancer.
1091
Howard M. Sandler Department of Radiation Oncology Cedars-Sinai Medical Center Los Angeles, California
REFERENCES 1. Trofimov A, Nguyen PL, Coen JJ et al: Radiotherapy treatment of early-stage prostate cancer with IMRT and protons: a treatment planning comparison. Int J Radiat Oncol Biol Phys 2007; 69: 444. 2. Colaco RJ, Hoppe BS, Flampouri S et al: Rectal toxicity after proton therapy for prostate cancer: an analysis of outcomes of prospective studies conducted at the University of Florida Proton Therapy Institute. Int J Radiat Oncol Biol Phys 2014; Epub ahead of print. 3. Harsolia A, Vargas C, Yan D et al: Predictors for chronic urinary toxicity after the treatment of prostate cancer with adaptive three-dimensional conformal radiotherapy: dose-volume analysis of a phase II dose-escalation study. Int J Radiat Oncol Biol Phys 2007; 69: 1100. 4. Yu JB, Soulos PR, Herrin J et al: Proton versus intensity-modulated radiotherapy for prostate cancer: patterns of care and early toxicity. JNCI 2013; 105: 25. 5. Sheets NC, Goldin GH, Meyer AM et al: Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and
morbidity and disease control in localized prostate cancer. JAMA 2012; 307: 1611. 6. al-Abany M, Helgason AR, Cronqvist AK et al: Toward a definition of a threshold for harmless doses to the anal-sphincter region and the rectum. Int J Radiat Oncol Biol Phys 2005; 61: 1035. 7. Resnick MJ and Penson DF: Functional outcomes after treatment for prostate cancer. N Engl J Med 2013; 368: 1654. 8. Krol R, Smeenk RJ, van Lin EN et al: Impact of late anorectal dysfunction on quality of life after pelvic radiotherapy. Int J Colorectal Dis 2013; 28: 519. 9. Hoppe BS, Michalski JM, Mendenhall NP et al: Comparative effectiveness study of patientreported outcomes after proton therapy or intensity-modulated radiotherapy for prostate cancer. Cancer 2014; 120: 1076. 10. Chung CS, Yock TI, Nelson K et al: Incidence of second malignancies among patients treated with proton versus photon radiation. Int J Radiat Oncol Biol Phys 2013; 87: 46.
11. King CR, Maxim PG, Hsu A et al: Incidental testicular irradiation from prostate IMRT: it all adds up. Int J Radiat Oncol Biol Phys 2010; 77: 484. 12. Nichols RC Jr, Morris CG, Hoppe BS et al: Proton radiotherapy for prostate cancer is not associated with post-treatment testosterone suppression. Int J Radiat Oncol Biol Phys 2012; 82: 1222. 13. Thompson I, Thrasher JB, Aus G et al: Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol 2007; 177: 2106. 14. Sanda MG, Dunn RL, Michalski J et al: Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008; 258: 1250. 15. Gray PJ, Paly JJ, Yeap BY et al: Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer. Cancer 2013; 119: 1729.
Radiation for Prostate Cancer: Intensity Modulated Radiation Therapy versus Proton Beam PROTON BEAM Proton therapy for the management of prostate cancer has been highly scrutinized because of its higher cost compared to photon based radiation therapies like intensity modulated radiation therapy (IMRT). The debate focuses on whether the benefits of proton therapy are worth the higher costs. If patients are treated with the same planning target volume margins, total dose (76 to 80 Gy) and target coverage, then proton therapy allows for a reduction in the radiation dose to the surrounding normal pelvic tissues in the low to moderate dose range of 0 to 50 Gy range compared to IMRT, while maintaining similar volumes of the organs at risk which receive higher doses (60 to 80 Gy).1 Consequently, the greatest advantage of proton therapy is in reducing the risk of side effects that may develop after exposure to 0 to 50 Gy radiation. Furthermore, this advantage might be magnified with the use of hypofractionated treatment. Unrealistic Expectations Rectal bleeding is the most common rectal toxicity, and the risk correlates with blood thinner use and volume of the rectum receiving 70e75 Gy.2 Importantly, proton therapy is not expected to lower the risk of rectal bleeding because it does not reduce the volume of the rectum receiving high doses of radiation compared with IMRT. Similarly, urinary toxicities like urethritis, urethral strictures and cystitis generally occur because of exposure of the urethra and/or bladder neck to high doses of radiation,3 and are not expected to be improved with proton therapy. Studies by Yu4 and Sheets5 et al confirmed these unrealistic expectations. These authors used the SEER (Surveillance, Epidemiology, and End Results)-Medicare database to compare IMRT with proton therapy in patients with prostate cancer and to evaluate toxicity based on ICD-9 codes. Interestingly, the ICD-9 codes they evaluated, such as rectal hemorrhage, ulcers and fistulas, were generally those that occur with high doses of radiation. Considering that patients receiving proton therapy were more likely to be on dose escalated clinical 0022-5347/15/1934-1089/0 THE JOURNAL OF UROLOGY® © 2015 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
trials, it is not surprising the investigators found no benefit and possibly worse toxicity with proton therapy, owing to a higher overall dose prescription among proton patients. Realistic Expectations Exposure of the organs at risk in the pelvis to 0 to 50 Gy radiation may lead to bowel urgency, bowel frequency, erectile dysfunction and secondary cancers.6 Resnick and Penson reported the 15-year functional outcomes after radiation therapy for localized prostate cancer and found that 16% of patients complained of moderate to severe issues with bowel frequency, bowel urgency and/or bowel pain.7 Unlike rectal bleeding, rectal urgency and frequency are generally problems that do not improve over time with further healing and may even worsen. Furthermore, urgency and incontinence were the bowel issues most highly associated with worse overall quality of life for patients irradiated for prostate cancer.8 Unfortunately, a major weakness of the SEER database studies comparing proton therapy and IMRT for prostate cancer is that they did not explore any differences in rectal urgency even though it has an ICD-9 code of 787.63.4 In comparison, in a study of 1,447 men treated with proton therapy or IMRT 15% treated with IMRT complained of moderate or severe problems with bowel urgency, as defined by the EPIC (Expanded Prostate Cancer Index Composite) questionnaire compared to 7% of men treated with proton therapy. Similarly, 10% of men treated with photon radiation complained of EPIC defined bowel frequency compared to 4% treated with proton therapy.9 These differences are statistically significant, clinically relevant and what we would expect based on the reduced volume of rectum receiving 0 to 50 Gy with proton therapy compared to IMRT. A reduced risk for secondary cancers is another potential advantage of proton therapy over photon radiation, particularly for younger men seeking an alternative to surgery. In a cohort study that included 33% of men treated for prostate cancer http://dx.doi.org/10.1016/j.juro.2015.01.069 Vol. 193, 1089-1091, April 2015 Printed in U.S.A.
www.jurology.com
j
1089
1090
OPPOSING VIEWS
proton therapy led to a 50% reduction in secondary cancers compared to photon based radiation.10 Sexual dysfunction is also an important side effect of radiation therapy which can be associated with low testosterone as a result of low photon scatter dose to the testis.11 In contrast, no significant decrease in median testosterone has been reported following proton therapy because it delivers little scatter radiation to the testicles.12 This difference may lead to improvement in sexual function in patients treated with proton therapy. In summary, while we should not overestimate the benefits of proton therapy, we should appreciate proton therapy for what we know it can do, which is significantly reduce the low to moderate doses of excess radiation delivered to organs at risk in the pelvis. This reduction in dose can lead to meaningful risk reductions in bowel urgency, bowel frequency, sexual dysfunction and secondary cancers compared with IMRT. Bradford S. Hoppe and Curtis Bryant University of Florida Proton Therapy Institute Jacksonville, Florida
IMRT Radiation therapy is a treatment modality that is widely acknowledged as effective in the management of prostate cancer.13 It is commonly and beneficially used against prostate cancer in the definitive setting (with the prostate in place) and in the adjuvant or salvage setting following radical prostatectomy. In the management of prostate cancer radiation therapy can be delivered with many different techniques, including photon external beam alone, 3-dimensional conformal therapy, proton beam, external beam in combination with brachytherapy (with either permanent radioactive seeds or high dose rate temporary) or brachytherapy alone. Each of these techniques can, when indicated, be combined with either short-term or long-term androgen deprivation. The potential combinations of modalities are great. However, there is a shortage of high quality comparative clinical trials, and so comparative assessment is often based on series from single institutions, often from experts in one area making valid comparisons challenging and raising questions about generalizability. The radiation oncology community would likely agree on the following 2 points. First, there is no inherent biological basis to expect that 1 Gy photon radiation is less effective than a comparable adjusted Gy of proton therapy. In fact, the dose delivered with proton therapy is carefully adjusted to make it equally tumoricidal compared to photon radiation so that 78 Gy photons (a typical dose for
prostate cancer) is equi-effective vs 78 Gy proton therapy. Second, there is agreement that 78 Gy is an effective treatment for most prostate cancer, regardless of whether proton therapy or IMRT with photons is used, ie there are no major claims that proton therapy at contemporary high doses are better at curing prostate cancer than IMRT when the same doses are used. In essence, the similarities between the 2 approaches are much greater than the putative differences. IMRT is well tolerated and has little adverse impact on patient reported quality of life among all of the relevant domains (bowel, bladder, sexual).14 If there are no known or claimed differences in tumor control between IMRT and proton therapy, are there differences in tolerability and posttreatment morbidity that would favor proton therapy? The radiation oncology community is sensitive to issues regarding post-radiotherapy morbidity, and a meaningful difference in quality of life outcomes favoring proton therapy would be a huge motivating factor towards wider adoption of proton therapy for prostate cancer. To date, based on recent crossinstitutional studies, one would need to conclude that such beneficial differences favoring proton beam do not exist. For example, in the SEER database study of IMRT and proton therapy, IMRT had a lower rate of gastrointestinal morbidity.5 Another study looking at Medicare beneficiaries revealed that there was no difference 12 months after treatment between IMRT and proton therapy for either gastrointestinal or genitourinary toxicity, while proton therapy cost Medicare nearly twice as much per patient treated.4 Finally, in a relatively small comparison study but one that had prospectively collected quality of life information, few differences were seen in quality of life regardless of what modality was used.15 Based upon these recent quality of life studies, one would not be able to conclude that proton therapy is superior to IMRT. Given the level of interest in the use of proton beam for prostate cancer, the existing data suggest that the hypothesis, proton therapy is superior to IMRT, is worth testing prospectively. In fact, there is an ongoing, National Cancer Institute funded, randomized, phase III trial of IMRT vs proton therapy for low and lowintermediate risk prostate cancer (NCT01617161). Since relatively early posttreatment quality of life is the primary end point of the study, outcomes should be available quickly following the accrual of subjects. In 2015 proton therapy is a more expensive modality than IMRT for prostate cancer. If proton treatment is no more effective than IMRT, then it is not cost-effective for prostate cancer. The incremental cost ratio equals the net cost/net benefit. If today there is a net cost for proton therapy above IMRT (and there is) and if the net benefit approaches
OPPOSING VIEWS
zero (as it may), then the incremental cost ratio for proton therapy approaches infinity and argues against widespread adoption of proton therapy for prostate cancer.
1091
Howard M. Sandler Department of Radiation Oncology Cedars-Sinai Medical Center Los Angeles, California
REFERENCES 1. Trofimov A, Nguyen PL, Coen JJ et al: Radiotherapy treatment of early-stage prostate cancer with IMRT and protons: a treatment planning comparison. Int J Radiat Oncol Biol Phys 2007; 69: 444. 2. Colaco RJ, Hoppe BS, Flampouri S et al: Rectal toxicity after proton therapy for prostate cancer: an analysis of outcomes of prospective studies conducted at the University of Florida Proton Therapy Institute. Int J Radiat Oncol Biol Phys 2014; Epub ahead of print. 3. Harsolia A, Vargas C, Yan D et al: Predictors for chronic urinary toxicity after the treatment of prostate cancer with adaptive three-dimensional conformal radiotherapy: dose-volume analysis of a phase II dose-escalation study. Int J Radiat Oncol Biol Phys 2007; 69: 1100. 4. Yu JB, Soulos PR, Herrin J et al: Proton versus intensity-modulated radiotherapy for prostate cancer: patterns of care and early toxicity. JNCI 2013; 105: 25. 5. Sheets NC, Goldin GH, Meyer AM et al: Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and
morbidity and disease control in localized prostate cancer. JAMA 2012; 307: 1611. 6. al-Abany M, Helgason AR, Cronqvist AK et al: Toward a definition of a threshold for harmless doses to the anal-sphincter region and the rectum. Int J Radiat Oncol Biol Phys 2005; 61: 1035. 7. Resnick MJ and Penson DF: Functional outcomes after treatment for prostate cancer. N Engl J Med 2013; 368: 1654. 8. Krol R, Smeenk RJ, van Lin EN et al: Impact of late anorectal dysfunction on quality of life after pelvic radiotherapy. Int J Colorectal Dis 2013; 28: 519. 9. Hoppe BS, Michalski JM, Mendenhall NP et al: Comparative effectiveness study of patientreported outcomes after proton therapy or intensity-modulated radiotherapy for prostate cancer. Cancer 2014; 120: 1076. 10. Chung CS, Yock TI, Nelson K et al: Incidence of second malignancies among patients treated with proton versus photon radiation. Int J Radiat Oncol Biol Phys 2013; 87: 46.
11. King CR, Maxim PG, Hsu A et al: Incidental testicular irradiation from prostate IMRT: it all adds up. Int J Radiat Oncol Biol Phys 2010; 77: 484. 12. Nichols RC Jr, Morris CG, Hoppe BS et al: Proton radiotherapy for prostate cancer is not associated with post-treatment testosterone suppression. Int J Radiat Oncol Biol Phys 2012; 82: 1222. 13. Thompson I, Thrasher JB, Aus G et al: Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol 2007; 177: 2106. 14. Sanda MG, Dunn RL, Michalski J et al: Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 2008; 258: 1250. 15. Gray PJ, Paly JJ, Yeap BY et al: Patient-reported outcomes after 3-dimensional conformal, intensity-modulated, or proton beam radiotherapy for localized prostate cancer. Cancer 2013; 119: 1729.
