- Email: [email protected]
Salvage radiotherapy: A plea for dose-escalation with intensity-modulated radiotherapy
European Journal of Cancer (2012) 48, 1415– 1416
Available at www.sciencedirect.com
journal homepage: www.ejconline.com
Letter to the Editor
Salvage radiotherapy: A plea for dose-escalation with intensity-modulated radiotherapy Piet Ost a,⇑, Cesare Cozzarini b, Alberto Bossi c, Gert De Meerleer a a
Department of Radiotherapy, Ghent University Hospital, Belgium Department of radiotherapy, Hospital San Raffaele, Milan, Italy c Department of Radiotherapy, Institut Gustave Roussy, Villejuif, France b
To the editor: We would like to congratulate Ohri et al. with their recent systematic review, addressing both the timing and dose of salvage radiotherapy (SRT) for prostate cancer.1 Their model confirms previous reports that the therapeutic ratio of SRT might be improved by initiating treatment at low prostate specific antigen (PSA) levels.1 More interestingly, they confirmed the data of King et al. that biochemical control rates increase with increasing SRT doses.2 The potential downside of dose-escalation is a higher rate of genitourinary (GU) and gastrointestinal (GI) toxicity. For example, it is estimated by Ohri et al. that dose-escalation above 72 Gy would result in an unacceptably high-rate of grade 3 toxicity (>20%),1 which would hamper dose-escalation when conventional radiotherapy techniques are used. However, the model of Ohri et al. is limited to papers reporting doses up to 70 Gy using conventional radiotherapy techniques. As the authors mention, the case for dose-escalation might be strengthened if modern treatment techniques are able to reduce long-term morbidity. Recently, two papers were published with a follow-up of 5 years exploring the potential benefit of intensity-modulated ⇑ Corresponding author: Address: Department of Radiotherapy, Ghent University Hospital, De Pintelaan 185, B-9000, Gent, Belgium. Tel.: +32 9 332 24 11; fax: +32 9 332 30 40. E-mail address: [email protected] (P. Ost).
0959-8049/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2012.01.024
radiotherapy (IMRT) in the postprostatectomy setting.3,4 IMRT allows the creation of concave dose distributions, which theoretically allow for a safe delivery of a higher dose to the target combined with a better sparing of the organs at risk (rectum and bladder).5 In the study of Goenka et al. an 8% reduction in late grade P2 GI toxicity was demonstrated with IMRT compared to 3D conformal radiotherapy.3 Only 1.4% of the patients experienced grade 3 GI toxicity, although the dose was escalated above 70 Gy.3 The potential benefit of doseescalation up to 76 Gy was just recently reported with a 5-year biochemical control rate of 73% when patients are treated before the PSA reaches 0.5 ng/ml.4 Moreover, it was pointed out that the fear of excess GI toxicity is not justified when IMRT is used with <1% grade 3 GI toxicity.4 On the other hand, IMRT might not be able to avoid an increase in GU toxicity as the bladder neck and vesicourethral anastomosis need to be included in the highdose region. In the paper of Goenka et al., IMRT was not able to reduce late grade P2 GU toxicity compared to patients treated with 3D conformal radiotherapy.3 Both in the paper of Goenka et al. and Ost et al. the incidence of late grade P2 GU was approximately three times the incidence of late grade P2 GI toxicity.3,4 However, a large proportion of late grade P2 GU side-effects were transient with only a minority of patients developing grade 3 GU toxicity (3%).4 These toxicity rates might be further improved in the near future when treatment
1416
Letter to the Editor / European Journal of Cancer 48 (2012) 1415–1416
margins are reduced in combination with image-guided 3D patient position verification systems.6,7 Consequently, high-dose SRT using IMRT appears to be safe,3,4 strengthening the case for a randomised trial addressing dose-escalation. The SAKK – SWISS group for clinical cancer research initiated such a trial randomising patients between 64 and 70 Gy (ClinicalTrials.gov: NCT01272050). It is hypothesised that with dose-escalation a 2.6 years improvement in freedom from biochemical relapse will be observed. Apparently, the majority of radiation oncologists in the United States are not waiting for the results of this trial, as they already use IMRT in their current practice to deliver doses of at least 70 Gy.8 Unfortunately, for patients referred with a PSA exceeding 1 ng/ml and/or a fast PSA doubling time, even dose-escalation might be insufficient.1,4 Although a proportion of these patients might still have a durable response with PB radiotherapy,4,9 the key question remains whether the PSA rise is reflective of local or distant progression. The first requirement is indeed the identification of patients without metastatic disease, as local salvage treatments would otherwise expose patients to unnecessary morbidity. New diagnostic imaging modalities, such as lymphotropic nanoparticle-enhanced magnetic resonance imaging, diffusionweighted magnetic resonance imaging and 11C-choline positron emitting tomography, that detects lymphatic and/or haematogenous metastases much earlier in the disease history are worth to be investigated to improve patient and target selection.10,11 Furthermore, it might be of interest for a subset of patients to expand the radiotherapy target to include the elective pelvic lymph nodes prone to harbour micrometastases,12 as failure of SRT is not necessarily due to extrapelvic disease. A randomisation between PB only and pelvic RT for patients destined to fail local PB SRT, based on the Stephenson nomogram,9 could test this hypothesis. For the time being, only one randomised trial (Radiation Therapy Oncology Group, RTOG 05-34) is accruing patients in the salvage setting comparing prostate bed only versus prostate bed and pelvic radiotherapy. Unfortunately, this trial will randomise the patients irrespective of the PSA kinetics. It is unlikely that prostate bed plus pelvic radiotherapy will benefit all patients. Finally, the role of androgen deprivation therapy (ADT) remains largely unresolved in the salvage setting. Several randomised trials are currently investigating the role of AD in this setting. The preliminary data of the RTOG 96-01 trial look promising.13 A reduced rate of biochemical and distant failures was observed with the addition of 2 years of bicalutamide after SRT (64.8 Gy), with a benefit for all subgroups. The role of ADT in combination with dose-escalation is currently
not under investigation in randomised trials, although the paper of Ost et al. showed an additional benefit of ADT even with high-dose radiotherapy. Conflict of interest statement None declared. References 1. Ohri N, Dicker AP, Trabulsi EJ, Showalter TN. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer 2011. 2. King CR, Kapp DS. Radiotherapy after prostatectomy: is the evidence for dose escalation out there? Int J Radiat Oncol Biol Phys 2008;71(2):346–50. 3. Goenka A, Magsanoc JM, Pei X, et al. Improved toxicity profile following high-dose postprostatectomy salvage radiation therapy with intensity-modulated radiation therapy. Eur Urol 2011. 4. Ost P, Lumen N, Goessaert AS, et al. High-dose salvage intensitymodulated radiotherapy with or without androgen deprivation after radical prostatectomy for rising or persisting prostate-specific antigen: 5-year results. Eur Urol 2011;60:842–9. 5. Koontz BF, Das S, Temple K, et al. Dosimetric and radiobiologic comparison of 3D conformal versus intensity modulated planning techniques for prostate bed radiotherapy. Med Dosim 2009;34(3):256–60. 6. Ost P, De Gersem W, De Potter B, et al. A comparison of the acute toxicity profile between two-dimensional and three-dimensional image-guided radiotherapy for postoperative prostate cancer. Clin Oncol (R Coll Radiol) 2011;23(5):344–9. 7. Ost P, De Meerleer G, De Gersem W, Impens A, De Neve W. Analysis of prostate bed motion using daily cone-beam computed tomography during postprostatectomy radiotherapy. Int J Radiat Oncol Biol Phys 2011;79(1):188–94. 8. Showalter TN, Ohri N, Teti KG, et al. Physician beliefs and practices for adjuvant and salvage radiation therapy after prostatectomy. Int J Radiat Oncol Biol Phys 2011. 9. Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25(15):2035–41. 10. Souvatzoglou M, Krause BJ, Purschel A, et al. Influence of (11)Ccholine PET/CT on the treatment planning for salvage radiation therapy in patients with biochemical recurrence of prostate cancer. Radiother Oncol 2011;99(2):193–200. 11. Meijer HJ, van Lin EN, Debats OA, et al. High occurrence of aberrant lymph node spread on magnetic resonance lymphography in prostate cancer patients with a biochemical recurrence after radical prostatectomy. Int J Radiat Oncol Biol Phys 2011. 12. Spiotto MT, Hancock SL, King CR. Radiotherapy after prostatectomy: improved biochemical relapse-free survival with whole pelvic compared with prostate bed only for high-risk patients. Int J Radiat Oncol Biol Phys 2007;69(1):54–61. 13. Shipley WU, Hunt D, Lukka HR, et al. Initial report of RTOG 9601, a phase III trial in prostate cancer: effect of anti-androgen therapy (AAT) with bicalutamide during and after radiation therapy (RT) on freedom from progression and incidence of metastatic disease in patients following radical prostatectomy (RP) with p T2–3, N0 disease and elevated PSA levels. J Clin Oncol 2011;29(Suppl. 7; abstr. 1).
Available at www.sciencedirect.com
journal homepage: www.ejconline.com
Letter to the Editor
Salvage radiotherapy: A plea for dose-escalation with intensity-modulated radiotherapy Piet Ost a,⇑, Cesare Cozzarini b, Alberto Bossi c, Gert De Meerleer a a
Department of Radiotherapy, Ghent University Hospital, Belgium Department of radiotherapy, Hospital San Raffaele, Milan, Italy c Department of Radiotherapy, Institut Gustave Roussy, Villejuif, France b
To the editor: We would like to congratulate Ohri et al. with their recent systematic review, addressing both the timing and dose of salvage radiotherapy (SRT) for prostate cancer.1 Their model confirms previous reports that the therapeutic ratio of SRT might be improved by initiating treatment at low prostate specific antigen (PSA) levels.1 More interestingly, they confirmed the data of King et al. that biochemical control rates increase with increasing SRT doses.2 The potential downside of dose-escalation is a higher rate of genitourinary (GU) and gastrointestinal (GI) toxicity. For example, it is estimated by Ohri et al. that dose-escalation above 72 Gy would result in an unacceptably high-rate of grade 3 toxicity (>20%),1 which would hamper dose-escalation when conventional radiotherapy techniques are used. However, the model of Ohri et al. is limited to papers reporting doses up to 70 Gy using conventional radiotherapy techniques. As the authors mention, the case for dose-escalation might be strengthened if modern treatment techniques are able to reduce long-term morbidity. Recently, two papers were published with a follow-up of 5 years exploring the potential benefit of intensity-modulated ⇑ Corresponding author: Address: Department of Radiotherapy, Ghent University Hospital, De Pintelaan 185, B-9000, Gent, Belgium. Tel.: +32 9 332 24 11; fax: +32 9 332 30 40. E-mail address: [email protected] (P. Ost).
0959-8049/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2012.01.024
radiotherapy (IMRT) in the postprostatectomy setting.3,4 IMRT allows the creation of concave dose distributions, which theoretically allow for a safe delivery of a higher dose to the target combined with a better sparing of the organs at risk (rectum and bladder).5 In the study of Goenka et al. an 8% reduction in late grade P2 GI toxicity was demonstrated with IMRT compared to 3D conformal radiotherapy.3 Only 1.4% of the patients experienced grade 3 GI toxicity, although the dose was escalated above 70 Gy.3 The potential benefit of doseescalation up to 76 Gy was just recently reported with a 5-year biochemical control rate of 73% when patients are treated before the PSA reaches 0.5 ng/ml.4 Moreover, it was pointed out that the fear of excess GI toxicity is not justified when IMRT is used with <1% grade 3 GI toxicity.4 On the other hand, IMRT might not be able to avoid an increase in GU toxicity as the bladder neck and vesicourethral anastomosis need to be included in the highdose region. In the paper of Goenka et al., IMRT was not able to reduce late grade P2 GU toxicity compared to patients treated with 3D conformal radiotherapy.3 Both in the paper of Goenka et al. and Ost et al. the incidence of late grade P2 GU was approximately three times the incidence of late grade P2 GI toxicity.3,4 However, a large proportion of late grade P2 GU side-effects were transient with only a minority of patients developing grade 3 GU toxicity (3%).4 These toxicity rates might be further improved in the near future when treatment
1416
Letter to the Editor / European Journal of Cancer 48 (2012) 1415–1416
margins are reduced in combination with image-guided 3D patient position verification systems.6,7 Consequently, high-dose SRT using IMRT appears to be safe,3,4 strengthening the case for a randomised trial addressing dose-escalation. The SAKK – SWISS group for clinical cancer research initiated such a trial randomising patients between 64 and 70 Gy (ClinicalTrials.gov: NCT01272050). It is hypothesised that with dose-escalation a 2.6 years improvement in freedom from biochemical relapse will be observed. Apparently, the majority of radiation oncologists in the United States are not waiting for the results of this trial, as they already use IMRT in their current practice to deliver doses of at least 70 Gy.8 Unfortunately, for patients referred with a PSA exceeding 1 ng/ml and/or a fast PSA doubling time, even dose-escalation might be insufficient.1,4 Although a proportion of these patients might still have a durable response with PB radiotherapy,4,9 the key question remains whether the PSA rise is reflective of local or distant progression. The first requirement is indeed the identification of patients without metastatic disease, as local salvage treatments would otherwise expose patients to unnecessary morbidity. New diagnostic imaging modalities, such as lymphotropic nanoparticle-enhanced magnetic resonance imaging, diffusionweighted magnetic resonance imaging and 11C-choline positron emitting tomography, that detects lymphatic and/or haematogenous metastases much earlier in the disease history are worth to be investigated to improve patient and target selection.10,11 Furthermore, it might be of interest for a subset of patients to expand the radiotherapy target to include the elective pelvic lymph nodes prone to harbour micrometastases,12 as failure of SRT is not necessarily due to extrapelvic disease. A randomisation between PB only and pelvic RT for patients destined to fail local PB SRT, based on the Stephenson nomogram,9 could test this hypothesis. For the time being, only one randomised trial (Radiation Therapy Oncology Group, RTOG 05-34) is accruing patients in the salvage setting comparing prostate bed only versus prostate bed and pelvic radiotherapy. Unfortunately, this trial will randomise the patients irrespective of the PSA kinetics. It is unlikely that prostate bed plus pelvic radiotherapy will benefit all patients. Finally, the role of androgen deprivation therapy (ADT) remains largely unresolved in the salvage setting. Several randomised trials are currently investigating the role of AD in this setting. The preliminary data of the RTOG 96-01 trial look promising.13 A reduced rate of biochemical and distant failures was observed with the addition of 2 years of bicalutamide after SRT (64.8 Gy), with a benefit for all subgroups. The role of ADT in combination with dose-escalation is currently
not under investigation in randomised trials, although the paper of Ost et al. showed an additional benefit of ADT even with high-dose radiotherapy. Conflict of interest statement None declared. References 1. Ohri N, Dicker AP, Trabulsi EJ, Showalter TN. Can early implementation of salvage radiotherapy for prostate cancer improve the therapeutic ratio? A systematic review and regression meta-analysis with radiobiological modelling. Eur J Cancer 2011. 2. King CR, Kapp DS. Radiotherapy after prostatectomy: is the evidence for dose escalation out there? Int J Radiat Oncol Biol Phys 2008;71(2):346–50. 3. Goenka A, Magsanoc JM, Pei X, et al. Improved toxicity profile following high-dose postprostatectomy salvage radiation therapy with intensity-modulated radiation therapy. Eur Urol 2011. 4. Ost P, Lumen N, Goessaert AS, et al. High-dose salvage intensitymodulated radiotherapy with or without androgen deprivation after radical prostatectomy for rising or persisting prostate-specific antigen: 5-year results. Eur Urol 2011;60:842–9. 5. Koontz BF, Das S, Temple K, et al. Dosimetric and radiobiologic comparison of 3D conformal versus intensity modulated planning techniques for prostate bed radiotherapy. Med Dosim 2009;34(3):256–60. 6. Ost P, De Gersem W, De Potter B, et al. A comparison of the acute toxicity profile between two-dimensional and three-dimensional image-guided radiotherapy for postoperative prostate cancer. Clin Oncol (R Coll Radiol) 2011;23(5):344–9. 7. Ost P, De Meerleer G, De Gersem W, Impens A, De Neve W. Analysis of prostate bed motion using daily cone-beam computed tomography during postprostatectomy radiotherapy. Int J Radiat Oncol Biol Phys 2011;79(1):188–94. 8. Showalter TN, Ohri N, Teti KG, et al. Physician beliefs and practices for adjuvant and salvage radiation therapy after prostatectomy. Int J Radiat Oncol Biol Phys 2011. 9. Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25(15):2035–41. 10. Souvatzoglou M, Krause BJ, Purschel A, et al. Influence of (11)Ccholine PET/CT on the treatment planning for salvage radiation therapy in patients with biochemical recurrence of prostate cancer. Radiother Oncol 2011;99(2):193–200. 11. Meijer HJ, van Lin EN, Debats OA, et al. High occurrence of aberrant lymph node spread on magnetic resonance lymphography in prostate cancer patients with a biochemical recurrence after radical prostatectomy. Int J Radiat Oncol Biol Phys 2011. 12. Spiotto MT, Hancock SL, King CR. Radiotherapy after prostatectomy: improved biochemical relapse-free survival with whole pelvic compared with prostate bed only for high-risk patients. Int J Radiat Oncol Biol Phys 2007;69(1):54–61. 13. Shipley WU, Hunt D, Lukka HR, et al. Initial report of RTOG 9601, a phase III trial in prostate cancer: effect of anti-androgen therapy (AAT) with bicalutamide during and after radiation therapy (RT) on freedom from progression and incidence of metastatic disease in patients following radical prostatectomy (RP) with p T2–3, N0 disease and elevated PSA levels. J Clin Oncol 2011;29(Suppl. 7; abstr. 1).