- Email: [email protected]
Low-dose-rate Brachytherapy, Radical Prostatectomy, or External-beam Radiation Therapy for Localised Prostate Carcinoma: The Growing Dilemma
EUROPEAN UROLOGY 60 (2011) 894–896
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 881–893 of this issue
Low-dose-rate Brachytherapy, Radical Prostatectomy, or External-beam Radiation Therapy for Localised Prostate Carcinoma: The Growing Dilemma Cesare Cozzarini * Department of Radiotherapy, San Raffaele Scientific Institute, Milan, Italy
A man with a newly diagnosed clinically localised prostatic carcinoma may be overwhelmed by the extreme variety of therapeutic options, including low-dose-rate and highdose-rate brachytherapy, radical prostatectomy (RP), either open or mini-invasive, external-beam radiation therapy (EBRT) with either three-dimensional conformal radiation therapy (3DCRT) or intensity-modulated radiation therapy (IMRT) technique, androgen-deprivation therapy and active surveillance. The elegant systematic review of Peinemann et al comparing LDR brachytherapy (LDR-BT), RP, and EBRT offers several reflections [1]. The authors refer to a dearth of long-term, adequately powered, randomised controlled trials (RCTs) analysing clinical outcome and toxicity profile following the three different treatment modalities. Of the 31 studies analysed, only one was in fact an RTC, whereas the remaining 30 referred to nonrandomised comparisons. Apart from known difficulties in conducting RCTs, such as physicians’ hesitancy to enrol patients in them owing to the concern over a possible deterioration of the patient– physician relationship, difficulty with informed consent, and a dislike of open discussions involving uncertainties [2], a growing phenomenon is emerging, as dramatically shown by the failure of the Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIRIT) study, prematurely closed after having accrued only 56 of the intended 1980 cases: patients are increasingly reluctant to be randomly assigned to different treatments [3]. This is particularly true for men with newly diagnosed localised prostate cancer (PCa), who represent an increasingly younger and better informed patient population, owing to the now ubiquitous
access to medical information (although potentially biased and inaccurate when derived from such unfiltered sources as the Internet) [4]. This increased patient autonomy is shifting the role of the physician towards that of an expert guide who should steer the patient towards the most appropriate treatment [4]. Nevertheless, increased patient awareness, which is determining the end of the era of physician paternalism, represents a growing difficulty—especially in North America—in terms of enrolling patients in RCTs comparing different treatment modalities [3]. The thorough review of Peinemann et al highlights the fact that the oncologic outcome following LDR-BT, RP, or EBRT for the treatment of localised PCa is virtually identical, provided that adequate irradiation doses are used for EBRT [1]. The superiority of LDR-BT over EBRT initially observed in older studies comparing LDR-BT, which from the beginning revealed its ability to deliver extremely high irradiation doses, to low-dose EBRT has subsequently diminished. The study of Kupelian et al, for example, reported a 7-yr biochemical relapse-free survival (bRFS) of 76%, 82%, 47%, and 77% ( p < 0.001) for RP, EBRT 72 Gy, EBRT < 72 Gy, and combined modality RT (LDR-BT plus EBRT). When EBRT <72 Gy was excluded from the analysis, no significant difference in terms of bRFS for different treatment modalities was found [5]. Even allowing for the possible uncertainty deriving from different definitions of biochemical recurrence (BCR) and from the uneven frequency of PSA testing, the likelihood of 5-yr BCR after RP, LDR-BT, or EBRT for the treatment of intermediate-risk PCa does not exceed 20% [6], and it
DOI of original article: 10.1016/j.eururo.2011.06.044 * Department of Radiotherapy, San Raffaele Scientific Institute. Via Olgettina, 60 20132, Milano, Italy. Tel. +39 02 2643 7647; Fax: +39 02 2643 7639. E-mail address: [email protected]. 0302-2838/$ – see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2011.08.004
EUROPEAN UROLOGY 60 (2011) 894–896
appears to be even lower for low-risk patients. In the quite unlikely hypothesis of local cancer recurrence after RP, EBRT is the more commonly adopted salvage treatment, with reported success rates of 50–60% in terms of 5-yr bRFS. The growing awareness of the key role of timely salvage irradiation, with PSA values ideally below 0.5–1 ng/ml, and of moderate dose escalation even in the postoperative setting may soon translate into even better clinical outcomes. Moreover, if delivered by means of modern IMRT techniques, the toxicity profile of high-dose salvage radiation therapy (RT) seems to be more than acceptable. Similarly, the 5-yr progression-free probability following salvage RP for locally recurrent PCa after RT is around 50–60%, even though the incidence of rectal injury, urinary incontinence, and anastomotic stricture may be high. Not surprisingly, the fear of cancer recurrence, which may cause severe psychological distress to PCa patients, who usually live several years after the initial diagnosis, seems to be slightly superior in patients undergoing irradiation—either BT or EBRT—than in those treated surgically [7]. With respect to the toxicity profile of the three different therapeutic approaches, the review underscores that grade 2–3 late urogenital toxicity was more common in the LDR-BT than the EBRT group, while for sexual function better scores were reported for patients undergoing LDR-BT when compared to the RP group. Urinary function and incontinence scores were also better for LDR-BT than for RP patients, whereas bowel function, which is known to be worse in irradiated than in surgically treated patients, was better in men treated with BT than in those undergoing EBRT [1]. The recent refinements in minimally invasive radical prostatectomy (MIRP) and the increasingly greater availability of highly sophisticated IMRT techniques, such as RapidArc and TomoTherapy, may lead in the near future to a rapid change in the relative differences in toxicity profile among the three therapeutic modalities. Although Malcolm et al recently reported better urinary and sexual function for LDR-BT compared to both open RP and robot assisted prostatectomy with the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA, USA) [8], it is easily foreseeable that with the improvement in the learning curve for MIRP the rate and the severity of both urinary incontinence and erectile dysfunction (ED) following MIRP may rapidly decline, thus becoming similar to that observed in patients undergoing LDR-BT. Similarly, the wider use of modern IMRT techniques, which allow a ‘‘sculpting’’ of high irradiation doses just around the tumour with extremely deep dose gradients similar, though not yet identical, to those achievable with brachytherapy, is leading to a rapid reduction in the incidence and the severity of acute and late gastrointestinal toxicity following high-dose EBRT. In addition, the introduction of magnetic resonance imaging in the simulation procedure allows a better identification of the penile bulb, leading to a significant reduction in unnecessary EBRT doses delivered not only to this but also to adjacent anatomic structures, such as neurovascular bundles, internal pudendal arteries, accessory
895
pudendal arteries, and corpora cavernosa—all potentially involved in the ethiopathogenesis of radiation-induced ED. This improved accuracy may thus lead to a risk of impotence following EBRT hopefully similar to that reported after both brachytherapy and modern MIRP. In contrast, higher EBRT doses may translate into a higher probability of irritative and obstructive urinary symptoms whose incidence and severity could theoretically approach that observed in patients undergoing brachytherapy. Nevertheless, it should be emphasised that newer therapeutic approaches such as MIRP, either laparoscopic or robot assisted, and IMRT represent more costly alternatives to more traditional counterparts (open RP and 3DCRT) [9]. Nguyen et al, analysing >45 000 patients 65 yr of age receiving definitive surgery or RT between 2002 and 2005 for clinically localised PCa, estimated the excess health care expenditures attributable to the increased utilisation of newer therapeutic modalities. They observed the rapidly increased utilisation of more expensive therapies over the study period, with MIRP representing 1.5% of the surgical treatments in 2002 versus 28.7% in 2005 and IMRT passing from 28.7% of EBRT in 2002 to 81.7% in 2005. Even among the subgroup of brachytherapy patients receiving additional EBRT, additional IMRT supplemented the implant in 18.7% of the cases in 2002 versus 70.2% in 2005 ( p < 0.001 in all cases). Predictors of utilisation of more costly therapies included living in an area with a median income of US$60 000 or more, living in a metropolitan rather than a rural area, having T1c disease, and being of Asian descent. Over the study period, the mean cost of each primary therapy significantly declined from 2002 to 2005: 3DCRT by 9%, IMRT by 15%, brachytherapy by 8%, brachytherapy plus IMRT by 16%, open RP by 9%, and MIRP by 23%. Nevertheless, newer and more expensive RT techniques remained costlier than their alternatives (plus US$10 000 for both IMRT vs 3DCRT and for brachytherapy plus IMRT vs brachytherapy plus 3DCRT), while at the end of 2005 the additional cost of MIRP in comparison to open RP was of only US$293. At the end of the study period, the cost of IMRT (more than US$30 000) was significantly higher than that of brachytherapy (roughly US$17 000) and RP, either open or MIRP (US$16 700 and US$16 500, respectively). Even allowing for the undeniable advantage in terms of improved toxicity profile of IMRT over 3DCRT and for the advantages of MIRP over open RP (reduced hospital stay, fewer transfusions, postoperative respiratory complications, and urethral strictures), an estimated national expenditure of more than US$350 million among American men diagnosed with PCa in 2005 suggests the need for increased comparative effectiveness research to accurately weigh costs and benefits, according to the authors’ conclusions [9]. The risk of a secondary cancer following the primary treatment of localised PCa should be finally addressed. Several studies showed a small but significant increase in secondary cancer, especially rectal and vesical, following irradiation, although no significant differences emerged between patients treated with EBRT or brachytherapy [10]. This additional late effect must in any case be incorporated into the cost–benefit analysis when considering the best
896
EUROPEAN UROLOGY 60 (2011) 894–896
treatment to suggest to an increasingly younger patient population with a 10-yr projected overall survival >90%.
[5] Kupelian PA, Potters L, Khuntia D, et al. Radical prostatectomy, external beam radiotherapy <72 Gy, external beam radiotherapy 72 Gy, permanent seed implantation, or combined seeds/external
Conflicts of interest: The author has nothing to disclose.
beam radiotherapy for stage T1-T2 prostate cancer. Int J Radiat Oncol Biol Phys 2004;58:25–33. [6] Vassil AD, Murphy ES, Reddy CA, et al. Five year biochemical
References
recurrence free survival for intermediate risk prostate cancer after radical prostatectomy, external beam radiation therapy or perma-
[1] Peinemann F, Grouven U, Bertel C, et al. Permanent interstitial low-
nent seed implantation. Urology 2010;76:1251–7.
dose-rate brachytherapy for patients with localised prostate cancer:
[7] Mehta SS, Lubeck DP, Pasta DJ, Litwin MS. Fear of cancer recurrence
a systematic review of randomised and nonrandomised controlled
in patients undergoing definitive treatment for prostate cancer:
clinical trials. Eur Urol 2011;60:881–93.
results from CaPSURE. J Urol 2003;170:1931–3.
[2] Taylor KM, Margolese RG, Soskolne CL. Physicians’ reasons for not
[8] Malcolm JB, Fabrizio MD, Barone BB, et al. Quality of life after open
entering eligible patients in a randomized clinical trial of surgery
or robotic prostatectomy, cryoablation or brachytherapy for local-
for breast cancer. N Engl J Med 1984;310:1363–7.
ized prostate cancer. J Urol 2010;183:1822–8.
[3] Crook JM, Gomez-Iturriaga A, Wallace K, et al. Comparison of
[9] Nguyen PL, Gu X, Lipsitz SR, et al. Cost implications of the rapid
health-related quality of life 5 years after SPIRIT: Surgical Prosta-
adoption of newer technologies for treating prostate cancer. J Clin
tectomy Versus Interstitial Radiation Intervention Trial. J Clin Oncol 2011;29:362–8.
Oncol 2011;29:1517–24. [10] Abdel-Wahab M, Reis IM, Hamilton K. Second primary cancer after
[4] Higham-Kessler J, Kodner IJ, Keune JD. Ethical counseling of an
radiotherapy for prostate cancer—a seer analysis of brachytherapy
indecisive patient with low-risk prostate carcinoma: a case study.
versus external beam radiotherapy. Int J Radiat Oncol Biol Phys
Surgery 2010;148:1022–5.
2008;72:58–68.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Editorial Referring to the article published on pp. 881–893 of this issue
Low-dose-rate Brachytherapy, Radical Prostatectomy, or External-beam Radiation Therapy for Localised Prostate Carcinoma: The Growing Dilemma Cesare Cozzarini * Department of Radiotherapy, San Raffaele Scientific Institute, Milan, Italy
A man with a newly diagnosed clinically localised prostatic carcinoma may be overwhelmed by the extreme variety of therapeutic options, including low-dose-rate and highdose-rate brachytherapy, radical prostatectomy (RP), either open or mini-invasive, external-beam radiation therapy (EBRT) with either three-dimensional conformal radiation therapy (3DCRT) or intensity-modulated radiation therapy (IMRT) technique, androgen-deprivation therapy and active surveillance. The elegant systematic review of Peinemann et al comparing LDR brachytherapy (LDR-BT), RP, and EBRT offers several reflections [1]. The authors refer to a dearth of long-term, adequately powered, randomised controlled trials (RCTs) analysing clinical outcome and toxicity profile following the three different treatment modalities. Of the 31 studies analysed, only one was in fact an RTC, whereas the remaining 30 referred to nonrandomised comparisons. Apart from known difficulties in conducting RCTs, such as physicians’ hesitancy to enrol patients in them owing to the concern over a possible deterioration of the patient– physician relationship, difficulty with informed consent, and a dislike of open discussions involving uncertainties [2], a growing phenomenon is emerging, as dramatically shown by the failure of the Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial (SPIRIT) study, prematurely closed after having accrued only 56 of the intended 1980 cases: patients are increasingly reluctant to be randomly assigned to different treatments [3]. This is particularly true for men with newly diagnosed localised prostate cancer (PCa), who represent an increasingly younger and better informed patient population, owing to the now ubiquitous
access to medical information (although potentially biased and inaccurate when derived from such unfiltered sources as the Internet) [4]. This increased patient autonomy is shifting the role of the physician towards that of an expert guide who should steer the patient towards the most appropriate treatment [4]. Nevertheless, increased patient awareness, which is determining the end of the era of physician paternalism, represents a growing difficulty—especially in North America—in terms of enrolling patients in RCTs comparing different treatment modalities [3]. The thorough review of Peinemann et al highlights the fact that the oncologic outcome following LDR-BT, RP, or EBRT for the treatment of localised PCa is virtually identical, provided that adequate irradiation doses are used for EBRT [1]. The superiority of LDR-BT over EBRT initially observed in older studies comparing LDR-BT, which from the beginning revealed its ability to deliver extremely high irradiation doses, to low-dose EBRT has subsequently diminished. The study of Kupelian et al, for example, reported a 7-yr biochemical relapse-free survival (bRFS) of 76%, 82%, 47%, and 77% ( p < 0.001) for RP, EBRT 72 Gy, EBRT < 72 Gy, and combined modality RT (LDR-BT plus EBRT). When EBRT <72 Gy was excluded from the analysis, no significant difference in terms of bRFS for different treatment modalities was found [5]. Even allowing for the possible uncertainty deriving from different definitions of biochemical recurrence (BCR) and from the uneven frequency of PSA testing, the likelihood of 5-yr BCR after RP, LDR-BT, or EBRT for the treatment of intermediate-risk PCa does not exceed 20% [6], and it
DOI of original article: 10.1016/j.eururo.2011.06.044 * Department of Radiotherapy, San Raffaele Scientific Institute. Via Olgettina, 60 20132, Milano, Italy. Tel. +39 02 2643 7647; Fax: +39 02 2643 7639. E-mail address: [email protected]. 0302-2838/$ – see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2011.08.004
EUROPEAN UROLOGY 60 (2011) 894–896
appears to be even lower for low-risk patients. In the quite unlikely hypothesis of local cancer recurrence after RP, EBRT is the more commonly adopted salvage treatment, with reported success rates of 50–60% in terms of 5-yr bRFS. The growing awareness of the key role of timely salvage irradiation, with PSA values ideally below 0.5–1 ng/ml, and of moderate dose escalation even in the postoperative setting may soon translate into even better clinical outcomes. Moreover, if delivered by means of modern IMRT techniques, the toxicity profile of high-dose salvage radiation therapy (RT) seems to be more than acceptable. Similarly, the 5-yr progression-free probability following salvage RP for locally recurrent PCa after RT is around 50–60%, even though the incidence of rectal injury, urinary incontinence, and anastomotic stricture may be high. Not surprisingly, the fear of cancer recurrence, which may cause severe psychological distress to PCa patients, who usually live several years after the initial diagnosis, seems to be slightly superior in patients undergoing irradiation—either BT or EBRT—than in those treated surgically [7]. With respect to the toxicity profile of the three different therapeutic approaches, the review underscores that grade 2–3 late urogenital toxicity was more common in the LDR-BT than the EBRT group, while for sexual function better scores were reported for patients undergoing LDR-BT when compared to the RP group. Urinary function and incontinence scores were also better for LDR-BT than for RP patients, whereas bowel function, which is known to be worse in irradiated than in surgically treated patients, was better in men treated with BT than in those undergoing EBRT [1]. The recent refinements in minimally invasive radical prostatectomy (MIRP) and the increasingly greater availability of highly sophisticated IMRT techniques, such as RapidArc and TomoTherapy, may lead in the near future to a rapid change in the relative differences in toxicity profile among the three therapeutic modalities. Although Malcolm et al recently reported better urinary and sexual function for LDR-BT compared to both open RP and robot assisted prostatectomy with the da Vinci Surgical System (Intuitive Surgical, Sunnyvale, CA, USA) [8], it is easily foreseeable that with the improvement in the learning curve for MIRP the rate and the severity of both urinary incontinence and erectile dysfunction (ED) following MIRP may rapidly decline, thus becoming similar to that observed in patients undergoing LDR-BT. Similarly, the wider use of modern IMRT techniques, which allow a ‘‘sculpting’’ of high irradiation doses just around the tumour with extremely deep dose gradients similar, though not yet identical, to those achievable with brachytherapy, is leading to a rapid reduction in the incidence and the severity of acute and late gastrointestinal toxicity following high-dose EBRT. In addition, the introduction of magnetic resonance imaging in the simulation procedure allows a better identification of the penile bulb, leading to a significant reduction in unnecessary EBRT doses delivered not only to this but also to adjacent anatomic structures, such as neurovascular bundles, internal pudendal arteries, accessory
895
pudendal arteries, and corpora cavernosa—all potentially involved in the ethiopathogenesis of radiation-induced ED. This improved accuracy may thus lead to a risk of impotence following EBRT hopefully similar to that reported after both brachytherapy and modern MIRP. In contrast, higher EBRT doses may translate into a higher probability of irritative and obstructive urinary symptoms whose incidence and severity could theoretically approach that observed in patients undergoing brachytherapy. Nevertheless, it should be emphasised that newer therapeutic approaches such as MIRP, either laparoscopic or robot assisted, and IMRT represent more costly alternatives to more traditional counterparts (open RP and 3DCRT) [9]. Nguyen et al, analysing >45 000 patients 65 yr of age receiving definitive surgery or RT between 2002 and 2005 for clinically localised PCa, estimated the excess health care expenditures attributable to the increased utilisation of newer therapeutic modalities. They observed the rapidly increased utilisation of more expensive therapies over the study period, with MIRP representing 1.5% of the surgical treatments in 2002 versus 28.7% in 2005 and IMRT passing from 28.7% of EBRT in 2002 to 81.7% in 2005. Even among the subgroup of brachytherapy patients receiving additional EBRT, additional IMRT supplemented the implant in 18.7% of the cases in 2002 versus 70.2% in 2005 ( p < 0.001 in all cases). Predictors of utilisation of more costly therapies included living in an area with a median income of US$60 000 or more, living in a metropolitan rather than a rural area, having T1c disease, and being of Asian descent. Over the study period, the mean cost of each primary therapy significantly declined from 2002 to 2005: 3DCRT by 9%, IMRT by 15%, brachytherapy by 8%, brachytherapy plus IMRT by 16%, open RP by 9%, and MIRP by 23%. Nevertheless, newer and more expensive RT techniques remained costlier than their alternatives (plus US$10 000 for both IMRT vs 3DCRT and for brachytherapy plus IMRT vs brachytherapy plus 3DCRT), while at the end of 2005 the additional cost of MIRP in comparison to open RP was of only US$293. At the end of the study period, the cost of IMRT (more than US$30 000) was significantly higher than that of brachytherapy (roughly US$17 000) and RP, either open or MIRP (US$16 700 and US$16 500, respectively). Even allowing for the undeniable advantage in terms of improved toxicity profile of IMRT over 3DCRT and for the advantages of MIRP over open RP (reduced hospital stay, fewer transfusions, postoperative respiratory complications, and urethral strictures), an estimated national expenditure of more than US$350 million among American men diagnosed with PCa in 2005 suggests the need for increased comparative effectiveness research to accurately weigh costs and benefits, according to the authors’ conclusions [9]. The risk of a secondary cancer following the primary treatment of localised PCa should be finally addressed. Several studies showed a small but significant increase in secondary cancer, especially rectal and vesical, following irradiation, although no significant differences emerged between patients treated with EBRT or brachytherapy [10]. This additional late effect must in any case be incorporated into the cost–benefit analysis when considering the best
896
EUROPEAN UROLOGY 60 (2011) 894–896
treatment to suggest to an increasingly younger patient population with a 10-yr projected overall survival >90%.
[5] Kupelian PA, Potters L, Khuntia D, et al. Radical prostatectomy, external beam radiotherapy <72 Gy, external beam radiotherapy 72 Gy, permanent seed implantation, or combined seeds/external
Conflicts of interest: The author has nothing to disclose.
beam radiotherapy for stage T1-T2 prostate cancer. Int J Radiat Oncol Biol Phys 2004;58:25–33. [6] Vassil AD, Murphy ES, Reddy CA, et al. Five year biochemical
References
recurrence free survival for intermediate risk prostate cancer after radical prostatectomy, external beam radiation therapy or perma-
[1] Peinemann F, Grouven U, Bertel C, et al. Permanent interstitial low-
nent seed implantation. Urology 2010;76:1251–7.
dose-rate brachytherapy for patients with localised prostate cancer:
[7] Mehta SS, Lubeck DP, Pasta DJ, Litwin MS. Fear of cancer recurrence
a systematic review of randomised and nonrandomised controlled
in patients undergoing definitive treatment for prostate cancer:
clinical trials. Eur Urol 2011;60:881–93.
results from CaPSURE. J Urol 2003;170:1931–3.
[2] Taylor KM, Margolese RG, Soskolne CL. Physicians’ reasons for not
[8] Malcolm JB, Fabrizio MD, Barone BB, et al. Quality of life after open
entering eligible patients in a randomized clinical trial of surgery
or robotic prostatectomy, cryoablation or brachytherapy for local-
for breast cancer. N Engl J Med 1984;310:1363–7.
ized prostate cancer. J Urol 2010;183:1822–8.
[3] Crook JM, Gomez-Iturriaga A, Wallace K, et al. Comparison of
[9] Nguyen PL, Gu X, Lipsitz SR, et al. Cost implications of the rapid
health-related quality of life 5 years after SPIRIT: Surgical Prosta-
adoption of newer technologies for treating prostate cancer. J Clin
tectomy Versus Interstitial Radiation Intervention Trial. J Clin Oncol 2011;29:362–8.
Oncol 2011;29:1517–24. [10] Abdel-Wahab M, Reis IM, Hamilton K. Second primary cancer after
[4] Higham-Kessler J, Kodner IJ, Keune JD. Ethical counseling of an
radiotherapy for prostate cancer—a seer analysis of brachytherapy
indecisive patient with low-risk prostate carcinoma: a case study.
versus external beam radiotherapy. Int J Radiat Oncol Biol Phys
Surgery 2010;148:1022–5.
2008;72:58–68.