- Email: [email protected]
Brachytherapy boost for prostate cancer: A potential conflict of disinterest
Brachytherapy
-
(2017) 1e2
Letter to the Editor
Brachytherapy boost for prostate cancer: A potential conflict of disinterest The role of brachytherapy boost (BB) for definitive irradiation of prostate cancer (PC) gains in popularity, due to rising proof levels in terms of biochemical control (1, 2). However, one might notice a decrease of BB’s application (3, 4), whereas high-proof level is now available to consider BB as a standard of care for intermediate and high-risk PC (1, 2). Regarding those new recommendations, a potential ‘‘conflict of disinterest’’ is emerging. In 2016, Orio PF et al. (5) observed that omission of BB for cervical cancer leads to a significant decrease of overall survival. Considering this element, we might worry about the consequences of keeping BB aside of PC irradiation. Insufficient care offer and nonadapted reimbursement appear to be the two main reasons explaining the suspected disinterest for BB. Care offer is facing an issue: is the number of Radiation Oncologists able to perform BB sufficient to take care of all the potential patients eligible for definitive PC irradiation? A recent European data coming from Borras JM et al. (6) reported that the number of PC irradiations in 2012 was 243,669 with a projection to the year 2025 of about 300,000 (þ25%). In 2012, in France, among the 192,769 irradiated patients, 27,630 were treated for PC (35,000 expected in 2025) (7). Considering that 50% of those patients were irradiated after radical prostatectomy or for metastatic disease, about 14,000 patients were treated by definitive irradiation (20,000 expected in 2025). According to this hypothesis, and estimating (optimistically) that among the 172 French radiation facilities, a maximum of 50 would be able to routinely provide BB; the estimated number of BB to perform in 2025, per week, per center, over 10 months, would then be ranged between 8 and 10. This high number of procedures may imply a deep reorganization of brachytherapy facilities, mainly in terms of trained human resources, to reach the balance between care offer and care demand. This analysis based on European and French data could easily be transposed to other countries, leading to consider the lack of care offer as a crucial obstacle preventing from BB’s adoption. Financial considerations represent the other key point impacting on the potential use of BB. Indeed, according to the French health care reimbursement system, a definitive external beam radiation therapy (EBRT), using intensity-modulated/image-guided technique, delivering a
total dose of 80 Gy (46 Gy þ 36 Gy as boost) in 40 fractions is reimbursed 16,000 V, whereas boost irradiation represents more or less 40% of the total amount (400 V 23 5 9200 V þ 400 V 17 5 6800 V). Are radiation therapy facilities (private or academic), without brachytherapy unit, willing to loose more than 40% of their PC treatment income by referring their patients to an external brachytherapy department? The economic obstacle would no longer exist for radiation therapy facilities, with brachytherapy unit, provided that BB’s reimbursement would be equivalent to the EBRT’s one. Among the important remaining questions, methodological and technical aspects appear preeminent. Regarding methodological approach, do we really have to wait for the results of other randomized trials (longer followup; significant improvement of overall survival) to unanimously accept BB in PC management? Maybe not; first, because BB dose is prescribed on the reference isodose and consequently, the dose delivered within the prostate will always be significantly higher (due to the hyperdosed volumes) than the homogeneous dose delivered by EBRT (brachytherapy being by itself an intrinsic dose-escalation technique) (8); second, because we already have consistent results coming from relevant retrospective studies which confirm that BB significantly impacts not only on biochemical control but also on clinical outcome (metastasis-free survival) (9). Regarding technical point of view, what could be the best choice between low (LDR) and high-dose rate (HDR) BB? Analysis of urinary toxicity, cost of the procedure, and training ability can help to answer this question. Concerning urinary toxicity, there is no phase III data demonstrating that late genito-urinary toxicities are lower with HDR than LDR. However, based on the two last published phase III randomized trials comparing EBRT vs. EBRT þ BB (10, 11), Chin et al. (1) suggested that the rate of late genito-urinary severe toxicities ($G3) could be higher after LDR-BB. Indeed, at 5 years, the rates of those toxicities are 8% vs. 18.4% for HDR and LDR respectively (10, 11). Even if the comparison of two different trial results is methodologically nonadequate, the use of graphical optimization with dwell-location and time-variation of the source allowed by HDR-BB may explain this difference. About cost analysis, are permanent implants less costeffective compared with temporary implants? A phase III trial with medico-economic analysis that randomizes for intermediate-risk PC, EBRT vs. EBRT þ BB (LDR or HDR) is currently recruiting (GETUGP05dClinicalTrials.gov Identifier: NCT02271659). The results of this trial will help to answer this critical question.
1538-4721/$ - see front matter Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2017.06.004
2
Letter to the Editor / Brachytherapy
Regarding brachytherapy training, the easier the technique will be to teach, the easier it will be to spread it. To date, whatever the BB technique (LDR or HDR), the skill of the brachytherapy team remains the most important factor allowing the achievement of an effective BB. For teams already trained for LDR brachytherapy, 30 consecutive HDR-BB seem acceptable to reach good quality implants in terms of dosimetric features (D90%, V100%, V150%, D2cc urethra) (12). Are we ready to acknowledge the new recommendations regarding BB for PC treatment using definitive irradiation (1, 2)? Improving care offer in the frame of adequate BB valorization will help to answer this crucial question. Health providers, insurers, and administrations have to be aware about this potential conflict of disinterest (causes and consequences), which should be positively dealt, to offer the best irradiation technique for prostate cancer treatment. Jean-Michel Hannoun-Levi Arthur Hannoun Department of Radiation Oncology Antoine Lacassagne Cancer Center & University of Cote d’Azur Nice, France
References [1] Chin J, Rumble RB, Kollmeier M, et al. Brachytherapy for patients with prostate cancer: American Society of clinical Oncology/cancer care Ontario Joint Guideline Update. J Clin Oncol 2017;35: 1737e1743.
-
(2017)
-e-
[2] Borras JM, Lievens Y, Barton M, et al. How many new cancer patients in Europe will require radiotherapy by 2025? An ESTROHERO analysis. Radiother Oncol 2016;119:5e11. [3] Key Words for Prostate Cancer. French National Cancer Institute;. Available at: http://www.e-cancer.fr/Patients-et-proches/Les-cancers/ Cancer-de-la-prostate/Points-cles. Accessed April 22, 2017. [4] Spratt DE, Soni PD, McLaughlin PW, et al. American Brachytherapy Society Task Group Report: Combination of brachytherapy and external beam radiation for high-risk prostate cancer. Brachytherapy 2017;16:1e12. [5] Orio PF 3rd, Nguyen PL, Buzurovic I, et al. The decreased use of brachytherapy boost for intermediate and high-risk prostate cancer despite evidence supporting its effectiveness. Brachytherapy 2016; 15:701e706. [6] Petereit DG, Frank SJ, Viswanathan AN, et al. Brachytherapy: where has it gone? J Clin Oncol 2015;33:980e982. [7] Han K, Milosevic M, Fyles A, et al. Trends in the utilization of brachytherapy in cervical cancer in the United States. Int J Radiat Oncol Biol Phys 2013;87:111e119. [8] Hannoun-Levi JM, Chand-Fouche ME, Dejean C, et al. Dose gradient impact on equivalent dose at 2 Gy for high dose rate interstitial brachytherapy. J Contemp Brachytherapy 2012;4:14e20. [9] Spratt DE, Zumsteg ZS, Ghadjar P, et al. Comparison of high-dose (86.4 Gy) IMRT vs combined brachytherapy plus IMRT for intermediate-risk prostate cancer. BJU Int 2014;114:360e367. [10] Hoskin PJ, Rojas AM, Bownes PJ, et al. Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer. Radiother Oncol 2012; 103:217e222. [11] Rodda S, Tyldesley S, Morris WJ, et al. ASCENDE-rt: an analysis of treatment-Related Morbidity for a randomized trial comparing a lowdose-rate brachytherapy boost with a dose-Escalated external beam boost for high- and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys 2017;98:286e295. [12] Benha€ım C, Chand ME, Gal J, et al. Prostate cancer boost using highdose-rate brachytherapy: impact of the learning curve on the dosimetry. Cancer Radiother 2014;18:659e665.
-
(2017) 1e2
Letter to the Editor
Brachytherapy boost for prostate cancer: A potential conflict of disinterest The role of brachytherapy boost (BB) for definitive irradiation of prostate cancer (PC) gains in popularity, due to rising proof levels in terms of biochemical control (1, 2). However, one might notice a decrease of BB’s application (3, 4), whereas high-proof level is now available to consider BB as a standard of care for intermediate and high-risk PC (1, 2). Regarding those new recommendations, a potential ‘‘conflict of disinterest’’ is emerging. In 2016, Orio PF et al. (5) observed that omission of BB for cervical cancer leads to a significant decrease of overall survival. Considering this element, we might worry about the consequences of keeping BB aside of PC irradiation. Insufficient care offer and nonadapted reimbursement appear to be the two main reasons explaining the suspected disinterest for BB. Care offer is facing an issue: is the number of Radiation Oncologists able to perform BB sufficient to take care of all the potential patients eligible for definitive PC irradiation? A recent European data coming from Borras JM et al. (6) reported that the number of PC irradiations in 2012 was 243,669 with a projection to the year 2025 of about 300,000 (þ25%). In 2012, in France, among the 192,769 irradiated patients, 27,630 were treated for PC (35,000 expected in 2025) (7). Considering that 50% of those patients were irradiated after radical prostatectomy or for metastatic disease, about 14,000 patients were treated by definitive irradiation (20,000 expected in 2025). According to this hypothesis, and estimating (optimistically) that among the 172 French radiation facilities, a maximum of 50 would be able to routinely provide BB; the estimated number of BB to perform in 2025, per week, per center, over 10 months, would then be ranged between 8 and 10. This high number of procedures may imply a deep reorganization of brachytherapy facilities, mainly in terms of trained human resources, to reach the balance between care offer and care demand. This analysis based on European and French data could easily be transposed to other countries, leading to consider the lack of care offer as a crucial obstacle preventing from BB’s adoption. Financial considerations represent the other key point impacting on the potential use of BB. Indeed, according to the French health care reimbursement system, a definitive external beam radiation therapy (EBRT), using intensity-modulated/image-guided technique, delivering a
total dose of 80 Gy (46 Gy þ 36 Gy as boost) in 40 fractions is reimbursed 16,000 V, whereas boost irradiation represents more or less 40% of the total amount (400 V 23 5 9200 V þ 400 V 17 5 6800 V). Are radiation therapy facilities (private or academic), without brachytherapy unit, willing to loose more than 40% of their PC treatment income by referring their patients to an external brachytherapy department? The economic obstacle would no longer exist for radiation therapy facilities, with brachytherapy unit, provided that BB’s reimbursement would be equivalent to the EBRT’s one. Among the important remaining questions, methodological and technical aspects appear preeminent. Regarding methodological approach, do we really have to wait for the results of other randomized trials (longer followup; significant improvement of overall survival) to unanimously accept BB in PC management? Maybe not; first, because BB dose is prescribed on the reference isodose and consequently, the dose delivered within the prostate will always be significantly higher (due to the hyperdosed volumes) than the homogeneous dose delivered by EBRT (brachytherapy being by itself an intrinsic dose-escalation technique) (8); second, because we already have consistent results coming from relevant retrospective studies which confirm that BB significantly impacts not only on biochemical control but also on clinical outcome (metastasis-free survival) (9). Regarding technical point of view, what could be the best choice between low (LDR) and high-dose rate (HDR) BB? Analysis of urinary toxicity, cost of the procedure, and training ability can help to answer this question. Concerning urinary toxicity, there is no phase III data demonstrating that late genito-urinary toxicities are lower with HDR than LDR. However, based on the two last published phase III randomized trials comparing EBRT vs. EBRT þ BB (10, 11), Chin et al. (1) suggested that the rate of late genito-urinary severe toxicities ($G3) could be higher after LDR-BB. Indeed, at 5 years, the rates of those toxicities are 8% vs. 18.4% for HDR and LDR respectively (10, 11). Even if the comparison of two different trial results is methodologically nonadequate, the use of graphical optimization with dwell-location and time-variation of the source allowed by HDR-BB may explain this difference. About cost analysis, are permanent implants less costeffective compared with temporary implants? A phase III trial with medico-economic analysis that randomizes for intermediate-risk PC, EBRT vs. EBRT þ BB (LDR or HDR) is currently recruiting (GETUGP05dClinicalTrials.gov Identifier: NCT02271659). The results of this trial will help to answer this critical question.
1538-4721/$ - see front matter Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2017.06.004
2
Letter to the Editor / Brachytherapy
Regarding brachytherapy training, the easier the technique will be to teach, the easier it will be to spread it. To date, whatever the BB technique (LDR or HDR), the skill of the brachytherapy team remains the most important factor allowing the achievement of an effective BB. For teams already trained for LDR brachytherapy, 30 consecutive HDR-BB seem acceptable to reach good quality implants in terms of dosimetric features (D90%, V100%, V150%, D2cc urethra) (12). Are we ready to acknowledge the new recommendations regarding BB for PC treatment using definitive irradiation (1, 2)? Improving care offer in the frame of adequate BB valorization will help to answer this crucial question. Health providers, insurers, and administrations have to be aware about this potential conflict of disinterest (causes and consequences), which should be positively dealt, to offer the best irradiation technique for prostate cancer treatment. Jean-Michel Hannoun-Levi Arthur Hannoun Department of Radiation Oncology Antoine Lacassagne Cancer Center & University of Cote d’Azur Nice, France
References [1] Chin J, Rumble RB, Kollmeier M, et al. Brachytherapy for patients with prostate cancer: American Society of clinical Oncology/cancer care Ontario Joint Guideline Update. J Clin Oncol 2017;35: 1737e1743.
-
(2017)
-e-
[2] Borras JM, Lievens Y, Barton M, et al. How many new cancer patients in Europe will require radiotherapy by 2025? An ESTROHERO analysis. Radiother Oncol 2016;119:5e11. [3] Key Words for Prostate Cancer. French National Cancer Institute;. Available at: http://www.e-cancer.fr/Patients-et-proches/Les-cancers/ Cancer-de-la-prostate/Points-cles. Accessed April 22, 2017. [4] Spratt DE, Soni PD, McLaughlin PW, et al. American Brachytherapy Society Task Group Report: Combination of brachytherapy and external beam radiation for high-risk prostate cancer. Brachytherapy 2017;16:1e12. [5] Orio PF 3rd, Nguyen PL, Buzurovic I, et al. The decreased use of brachytherapy boost for intermediate and high-risk prostate cancer despite evidence supporting its effectiveness. Brachytherapy 2016; 15:701e706. [6] Petereit DG, Frank SJ, Viswanathan AN, et al. Brachytherapy: where has it gone? J Clin Oncol 2015;33:980e982. [7] Han K, Milosevic M, Fyles A, et al. Trends in the utilization of brachytherapy in cervical cancer in the United States. Int J Radiat Oncol Biol Phys 2013;87:111e119. [8] Hannoun-Levi JM, Chand-Fouche ME, Dejean C, et al. Dose gradient impact on equivalent dose at 2 Gy for high dose rate interstitial brachytherapy. J Contemp Brachytherapy 2012;4:14e20. [9] Spratt DE, Zumsteg ZS, Ghadjar P, et al. Comparison of high-dose (86.4 Gy) IMRT vs combined brachytherapy plus IMRT for intermediate-risk prostate cancer. BJU Int 2014;114:360e367. [10] Hoskin PJ, Rojas AM, Bownes PJ, et al. Randomised trial of external beam radiotherapy alone or combined with high-dose-rate brachytherapy boost for localised prostate cancer. Radiother Oncol 2012; 103:217e222. [11] Rodda S, Tyldesley S, Morris WJ, et al. ASCENDE-rt: an analysis of treatment-Related Morbidity for a randomized trial comparing a lowdose-rate brachytherapy boost with a dose-Escalated external beam boost for high- and intermediate-risk prostate cancer. Int J Radiat Oncol Biol Phys 2017;98:286e295. [12] Benha€ım C, Chand ME, Gal J, et al. Prostate cancer boost using highdose-rate brachytherapy: impact of the learning curve on the dosimetry. Cancer Radiother 2014;18:659e665.