- Email: [email protected]
Prostate-specific antigen following radiation therapy
Int. I. Radiation Oncology
PII: SO360-3016(96)00397-5
ELSEVIER
l
Biol. Phys., Vol. 36, No. 3, pp. 749-751, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/96 $15.03 + .IXI
Editorial PROSTATE-SPECIFIC
ANTIGEN RICHARD
FOLLOWING
E. PESCHEL,
M.D.,
RADIATION
THERAPY
PH.D.
Yale University School of Medicine, New Haven, CT Historically, conventional external beam radiation therapy (RT) has been an important therapeutic modality for early prostate cancer. Although the true therapeutic value of RT remains a point of controversy (1, 8), RT is the treatment of choice for many patients (5, 13). For example, for elderly patients (average age: 69 years) with Stage Tl and T2 disease treated with RT, the lo-year adjusted survival (AS) rate is 70% and the lo-year clinical local control rate is 88% (5). However, during the last 5 years, the prostatespecific antigen (PSA) has dramatically changed our understanding of clinically localized prostate cancer. First, for clinical Stage Tl, T2, and T3 disease treated with RT, the pretreatment PSA is a very strong predictor of ultimate long-term clinical outcome (11, 21). Based on the data from Kuban et al. (ll), RT patients with a pretreatment PSA < 4 rig/ml have a lo-year clinical disease-free (NED) survival rate of 80% and a IO-year biochemical diseasefree (bNED) survival rate of 59% compared to a IO-year NED survival rate of only 13-23% and a lo-year bNED survival rate of 0% for patients with a pretreatment PSA > 10 rig/ml. Of course, the same paradigm applies to radical prostatectomy (RP) patients. Surgical patients with a pretreatment PSA > lo-12 rig/ml have a 75-80% probability of being upstaged at the time of RP and these patients are at high risk for long-term clinical failure (4, 12). Second, the use of the posttreatment PSA to evaluate loyear bNED survival for both RT and RP documents that only a modest fraction of early prostate cancer patients may be ultimately cured with either modality (15, 17, 19). For RT patients with Tl-T3 disease, only lo-30% may be biochemically disease-free at 10 years (15, 17). For RP patients with favorable Tl and T2 disease, the lo-year bNED survival rate is only 41% (19). These data have stimulated interest in new methods that may safely increase the radiation dose to the prostate compared to conventional doses of 6,500 cGy to 7,000 cGy (at 180 cGy to 200 cGy per fraction). These new methods include transperineal prostate implant, dose escalation 3D conforma1 therapy, and neutron or proton beam radiotherapy (2, 6, 14, 16, 18).
While the PSA has provided us with many new insights, it also has created new dilemmas for radiation oncologists. One of the most important problems which the PSA creates is how to interpret early posttreatment PSA profiles in terms of long-term clinical outcome (3). In this issue of the International Journal of Radiation Oncology Biology and Physics, Horwitz et al. (7) have successfully addressed many of the problems with the interpretation of the posttreatment PSA. First and most important, there is currently no standard definition of bNED. Horwitz et al. (7) highlight this problem by comparing five different definitions of bNED used at five different institutions. A variety of other definitions such as PSA < 4 rig/ml have been used in the radiation therapy literature (20). Because there are several continuous variables necessary to define bNED including PSA threshold or nadir (i.e., PSA < 4 rig/ml to PSA < 1 ng/rnl) and the PSA change following a PSA nadir (i.e., two successive increases, any increase >l rig/ml, >50% increase, etc.), there are literally hundreds of possible definitions for bNED. Some authors have simply defined bNED based on a very low posttreatment PSA value such as
Reprint requeststo: Richard E. Peschel, M.D., Ph.D., Professor of Therapeutic
Radiology,
Yale University
333 Cedar Street, New Haven, CT 06510.
School of Medicine,
Accepted for publication 149
1 August 1996.
750
I. J. Radiation Oncology 0 Biology 0 Physics
tween any definition of bNED and long-term AS is complex. Second, Horwitz et al. (7) have dramatically demonstrated “that statistically significant differences in outcome can be obtained merely by changing the definition of biochemical control.” This has the potential for the manipulation of data to produce overly optimistic or overly pessimistic treatment outcomes. Indeed, as Horwitz et al. (7) note in their discussion, one can change treatment outcome by a factor of 10 with subtle changes in the definition of bNED (9). In addition, they have shown that the differences in outcome that result from using different definitions of bNED are a function of T stage, Gleason score, and pretreatment PSA. Finally, these authors correctly conclude that “until a standardized definition of biochemical control is adopted, differences in therapeutic outcome between various treatment modalities or institutions cannot be meaningfully compared.” This is particularly true as we attempt to compare the various treatment outcomes of RP vs. transperineal implant vs. 3D conformal therapy based on different definitions of bNED. The Horwitz et al. (7) publication helps clarify many of the current problems with the reporting of bNED data. I would add the following addendum to this excellent article: a) Radiation oncologists should establish a consensus on a single definition of bNED and agree
Volume 36, Number 3, 1996
to a consistent format for reporting posttreatment PSA data; b) radiation oncologists should view with caution the claims of successful therapy based solely on single arm studies reporting short-term bNED data. There is currently no single definition of bNED that accurately predicts long-term AS for all of the various subgroups of patients when stratified by age, T stage, Gleason score, and pretreatment PSA; c) PSA posttreatment profiles and bNED are not substitutes for well designed prospective clinical trials. In a recent publication from M. D. Anderson, Pollack et al. (14) reported their early results with 3D conformal therapy. At 6 months following therapy, 90% of the patients treated with 3D conformal therapy achieved a PSA < 4 rig/ml and 53% had a PSA < 2 rig/ml. In a single arm trial, these results could have been interpreted as a success for 3D conformal therapy. However, the M. D. Anderson trial was randomized between conventional RT and 3D conforma1 therapy. No significant difference was noted between the two arms of the study because in the conventional RT group, 94% of patients achieved a PSA < 4 rig/ml and 72% had a PSA < 2 rig/ml (14). Although the results of this trial are still preliminary, it emphasizes the differences in conclusions that are often reached in single-arm studies compared to prospective randomized trials. Posttreatment PSA and bNED data will never be able to nullify this scientific paradigm.
REFERENCES 1. Adolfson, J.; Steineck, G.; Whitmore, W. F. Recent results of management of palpable clinically localized prostate cancer. Cancer 72:310-322; 1993. 2. Blasko, J. C.; Grimm, P. D.; Ragde,H. Brachytherapyand organpreservationin the managementof carcinomaof the prostate.Semin.Radiat.Oncol. 3:240-249; 1993. 3. Ennis, R. D.; Fischer,D. B.; Peschel,R. E. Early prostate specific antigen(PSA) responsepredictsPSA nadir in patients with prostatecancertreatedwith externalbeamradiation. Radiat.Oncol. Invest. 3:179-184; 1995. 4. Ennis, R. D.; Flynn, S. D.; Fischer, D. B.; Peschel,R. E. Preoperativeserumprostate-specificantigen and gleason gradeas predictorsof pathologic stagein clinically organ confinedprostatecancer:Implicationsfor the choiceof primary treatment.Int. J. Radiat. Oncol. Biol. Phys. 30:317322; 1994. 5. Ennis, R. D.; Peschel,R. E. Radiationtherapy for prostate cancer.Cancer72:2644-2650;1993. 6. Forman,J. D.; Dulcos,M.; Shamsa,F.; Porter, A. T.; Orton, C. Hyperfractionatedconformalradiotherapyin locally advancedprostatecancer:Resultsof a doseescalationstudy. Int. J. Radiat.Oncol. Biol. Phys. 34655-662; 1996. 7. Horwitz, E.; Ziaja, E.; Vicini, F.; Gonzalez,J.; Dmuchowski, C.; Stromberg,J.; Brabbins,D.; Hollander,J.; Chen,P.;Martinez, A. Assessingthe variability of outcomefor patients treatedwith localizedprostateirradiationusingdifferentdefinitions of biochemicalcontrol. Int. J. Radiat.Oncol. Biol. Phys.36:565-571;1996. 8. Johansson, J. E.; Adami, H. 0.; Andersson,S.0.; Bergshom, R.; Holmberg,L.; Krusemo,U. B. High lo-year survivalrate
in patients with early, untreatedprostatic cancer.JAMA 267:2191-2196;1992. 9. Kaplan, I. D.; Cox, R. S.; Bagshaw,M. A. Prostatespecific antigenafterexternalbeamradiotherapyfor prostaticcancer: Followup. J. Urol. 149:519-522;1993. 10. Kavadi, V. S.; Zagars,G. K.; Pollack, A. Serumprostatespecific antigenafter radiation therapy for clinically localized prostatecancer:Prognosticimplications.Int. J. Radiat. Oncol. Biol. Phys. 30:279-287; 1994. 11. Kuban, D. A.; El-Mahdi, A. M.; Schellhammer,P. F. Prostate-specificantigen for pretreatmentprediction and posttreatmentevaluationof outcomeafter definitive irradiation for prostatecancer.Int. J. Radiat.Oncol. Biol. Phys.32:307316; 1995. 12. Peschel,R. E. Prostate-specificantigen: Clinical versus pathologicalstage.Int. J. Radiat.Oncol. Biol. Phys. 30:493494; 1994. 13. Peschel,R. E.; Wilson,L.; Haffty, B.; Papadopoulis, D.; Rosenzweig,K.; Feltes,M. The effect of advancedageon the efficacy of radiation therapy for early breastcancer,local prostatecancerandgradeIII-IV gliomas.Int. J. Radiat.Oncol. Biol. Phys. 261539-544;1993. 14. Pollack,A.; Zagars,G. K.; Starkschall,G.; Childress,C. H.; Kopplin, S.; Boyer, A. L.; Rosen,I. I. Conventionalvs. conformal radiotherapyfor prostatecancer:Preliminaryresults of dosimetryand acute toxicity. Int. J. Radiat.Oncol. Biol. Phys.34:555-564; 1996. 15. Rosenzweig,K. E.; Morgan, W. R.; Lytton, B.; Peschel, R. E. Prostatespecificantigen following radiotherapyfor local prostatecancer.J. Urol. 153:1561-1564;1995.
PSA following RT 0 R. E. 16. Russell, K. J.; Caplan, R. J.; Laramore, G. E.; Bumison, C. M.; Maor, M. H.; Taylor, M. E.; Zink, S.; Davis, L. W.; Griffin, T. W. Photons vs. fast neutron external beam radiotherapy in the treatment of locally advanced prostate cancer: Results of a randomized prospective trial. Int. J. Radiat. Oncol. Biol. Phys. 28:47-54; 1994. 17. Schellhammer, P. F.; El-Mahdi, A. M.; Wright, G. L.; Kolm, P.; Ragle, R. Prostate-specific antigen to determine progression-free survival after radiation therapy for localized carcinoma of prostate. Urol. 42:13-19; 1993. 18. Shipley, W. U.; Verhey, L. J.; Munzenrider, J. E.; Suit, H. D.; Urie, M. M.; McManus, P. L.; Young, R. H.; Shipley, J. W.; Zietman, A. L.; Biggs, B. J.; Heney, N. M.; Gottein, M. Advanced prostate cancer: The results of a randomized comparative trial of high dose irradiation boosting with con-
PESCHEL
751
formal protons compared with conventional dose irradiation using photons alone. Int. J. Radiat. Oncol. Biol. Phys. 32:312; 1995. 19. Stein, A.; DeKernion, J. B.; Smith, R. B.; Dorey, F.; Patel, H. Prostate specific antigen levels after radical prostatectomy in patients with organ confined and locally extensive prostate cancer. J. Urol. 147:942-946; 1992. 20. Wilson, L. D.; Ennis, R.; Percarpio, B.; Peschel, R. E. Location of the prostatic apex and its relationship to the ischial tuberosities. Int. J. Radiat. Oncol. Biol. Phys. 29: 1133-l 138; 1994. 21. Zagars, G. K.; Pollack, A.; Kavadi, V. S.; von Eshenbach, A. C. Prostate-specific antigen and radiation therapy for clinically localized prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 32:293-306; 1995.
PII: SO360-3016(96)00397-5
ELSEVIER
l
Biol. Phys., Vol. 36, No. 3, pp. 749-751, 1996 Copyright 0 1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/96 $15.03 + .IXI
Editorial PROSTATE-SPECIFIC
ANTIGEN RICHARD
FOLLOWING
E. PESCHEL,
M.D.,
RADIATION
THERAPY
PH.D.
Yale University School of Medicine, New Haven, CT Historically, conventional external beam radiation therapy (RT) has been an important therapeutic modality for early prostate cancer. Although the true therapeutic value of RT remains a point of controversy (1, 8), RT is the treatment of choice for many patients (5, 13). For example, for elderly patients (average age: 69 years) with Stage Tl and T2 disease treated with RT, the lo-year adjusted survival (AS) rate is 70% and the lo-year clinical local control rate is 88% (5). However, during the last 5 years, the prostatespecific antigen (PSA) has dramatically changed our understanding of clinically localized prostate cancer. First, for clinical Stage Tl, T2, and T3 disease treated with RT, the pretreatment PSA is a very strong predictor of ultimate long-term clinical outcome (11, 21). Based on the data from Kuban et al. (ll), RT patients with a pretreatment PSA < 4 rig/ml have a lo-year clinical disease-free (NED) survival rate of 80% and a IO-year biochemical diseasefree (bNED) survival rate of 59% compared to a IO-year NED survival rate of only 13-23% and a lo-year bNED survival rate of 0% for patients with a pretreatment PSA > 10 rig/ml. Of course, the same paradigm applies to radical prostatectomy (RP) patients. Surgical patients with a pretreatment PSA > lo-12 rig/ml have a 75-80% probability of being upstaged at the time of RP and these patients are at high risk for long-term clinical failure (4, 12). Second, the use of the posttreatment PSA to evaluate loyear bNED survival for both RT and RP documents that only a modest fraction of early prostate cancer patients may be ultimately cured with either modality (15, 17, 19). For RT patients with Tl-T3 disease, only lo-30% may be biochemically disease-free at 10 years (15, 17). For RP patients with favorable Tl and T2 disease, the lo-year bNED survival rate is only 41% (19). These data have stimulated interest in new methods that may safely increase the radiation dose to the prostate compared to conventional doses of 6,500 cGy to 7,000 cGy (at 180 cGy to 200 cGy per fraction). These new methods include transperineal prostate implant, dose escalation 3D conforma1 therapy, and neutron or proton beam radiotherapy (2, 6, 14, 16, 18).
While the PSA has provided us with many new insights, it also has created new dilemmas for radiation oncologists. One of the most important problems which the PSA creates is how to interpret early posttreatment PSA profiles in terms of long-term clinical outcome (3). In this issue of the International Journal of Radiation Oncology Biology and Physics, Horwitz et al. (7) have successfully addressed many of the problems with the interpretation of the posttreatment PSA. First and most important, there is currently no standard definition of bNED. Horwitz et al. (7) highlight this problem by comparing five different definitions of bNED used at five different institutions. A variety of other definitions such as PSA < 4 rig/ml have been used in the radiation therapy literature (20). Because there are several continuous variables necessary to define bNED including PSA threshold or nadir (i.e., PSA < 4 rig/ml to PSA < 1 ng/rnl) and the PSA change following a PSA nadir (i.e., two successive increases, any increase >l rig/ml, >50% increase, etc.), there are literally hundreds of possible definitions for bNED. Some authors have simply defined bNED based on a very low posttreatment PSA value such as
Reprint requeststo: Richard E. Peschel, M.D., Ph.D., Professor of Therapeutic
Radiology,
Yale University
333 Cedar Street, New Haven, CT 06510.
School of Medicine,
Accepted for publication 149
1 August 1996.
750
I. J. Radiation Oncology 0 Biology 0 Physics
tween any definition of bNED and long-term AS is complex. Second, Horwitz et al. (7) have dramatically demonstrated “that statistically significant differences in outcome can be obtained merely by changing the definition of biochemical control.” This has the potential for the manipulation of data to produce overly optimistic or overly pessimistic treatment outcomes. Indeed, as Horwitz et al. (7) note in their discussion, one can change treatment outcome by a factor of 10 with subtle changes in the definition of bNED (9). In addition, they have shown that the differences in outcome that result from using different definitions of bNED are a function of T stage, Gleason score, and pretreatment PSA. Finally, these authors correctly conclude that “until a standardized definition of biochemical control is adopted, differences in therapeutic outcome between various treatment modalities or institutions cannot be meaningfully compared.” This is particularly true as we attempt to compare the various treatment outcomes of RP vs. transperineal implant vs. 3D conformal therapy based on different definitions of bNED. The Horwitz et al. (7) publication helps clarify many of the current problems with the reporting of bNED data. I would add the following addendum to this excellent article: a) Radiation oncologists should establish a consensus on a single definition of bNED and agree
Volume 36, Number 3, 1996
to a consistent format for reporting posttreatment PSA data; b) radiation oncologists should view with caution the claims of successful therapy based solely on single arm studies reporting short-term bNED data. There is currently no single definition of bNED that accurately predicts long-term AS for all of the various subgroups of patients when stratified by age, T stage, Gleason score, and pretreatment PSA; c) PSA posttreatment profiles and bNED are not substitutes for well designed prospective clinical trials. In a recent publication from M. D. Anderson, Pollack et al. (14) reported their early results with 3D conformal therapy. At 6 months following therapy, 90% of the patients treated with 3D conformal therapy achieved a PSA < 4 rig/ml and 53% had a PSA < 2 rig/ml. In a single arm trial, these results could have been interpreted as a success for 3D conformal therapy. However, the M. D. Anderson trial was randomized between conventional RT and 3D conforma1 therapy. No significant difference was noted between the two arms of the study because in the conventional RT group, 94% of patients achieved a PSA < 4 rig/ml and 72% had a PSA < 2 rig/ml (14). Although the results of this trial are still preliminary, it emphasizes the differences in conclusions that are often reached in single-arm studies compared to prospective randomized trials. Posttreatment PSA and bNED data will never be able to nullify this scientific paradigm.
REFERENCES 1. Adolfson, J.; Steineck, G.; Whitmore, W. F. Recent results of management of palpable clinically localized prostate cancer. Cancer 72:310-322; 1993. 2. Blasko, J. C.; Grimm, P. D.; Ragde,H. Brachytherapyand organpreservationin the managementof carcinomaof the prostate.Semin.Radiat.Oncol. 3:240-249; 1993. 3. Ennis, R. D.; Fischer,D. B.; Peschel,R. E. Early prostate specific antigen(PSA) responsepredictsPSA nadir in patients with prostatecancertreatedwith externalbeamradiation. Radiat.Oncol. Invest. 3:179-184; 1995. 4. Ennis, R. D.; Flynn, S. D.; Fischer, D. B.; Peschel,R. E. Preoperativeserumprostate-specificantigen and gleason gradeas predictorsof pathologic stagein clinically organ confinedprostatecancer:Implicationsfor the choiceof primary treatment.Int. J. Radiat. Oncol. Biol. Phys. 30:317322; 1994. 5. Ennis, R. D.; Peschel,R. E. Radiationtherapy for prostate cancer.Cancer72:2644-2650;1993. 6. Forman,J. D.; Dulcos,M.; Shamsa,F.; Porter, A. T.; Orton, C. Hyperfractionatedconformalradiotherapyin locally advancedprostatecancer:Resultsof a doseescalationstudy. Int. J. Radiat.Oncol. Biol. Phys. 34655-662; 1996. 7. Horwitz, E.; Ziaja, E.; Vicini, F.; Gonzalez,J.; Dmuchowski, C.; Stromberg,J.; Brabbins,D.; Hollander,J.; Chen,P.;Martinez, A. Assessingthe variability of outcomefor patients treatedwith localizedprostateirradiationusingdifferentdefinitions of biochemicalcontrol. Int. J. Radiat.Oncol. Biol. Phys.36:565-571;1996. 8. Johansson, J. E.; Adami, H. 0.; Andersson,S.0.; Bergshom, R.; Holmberg,L.; Krusemo,U. B. High lo-year survivalrate
in patients with early, untreatedprostatic cancer.JAMA 267:2191-2196;1992. 9. Kaplan, I. D.; Cox, R. S.; Bagshaw,M. A. Prostatespecific antigenafterexternalbeamradiotherapyfor prostaticcancer: Followup. J. Urol. 149:519-522;1993. 10. Kavadi, V. S.; Zagars,G. K.; Pollack, A. Serumprostatespecific antigenafter radiation therapy for clinically localized prostatecancer:Prognosticimplications.Int. J. Radiat. Oncol. Biol. Phys. 30:279-287; 1994. 11. Kuban, D. A.; El-Mahdi, A. M.; Schellhammer,P. F. Prostate-specificantigen for pretreatmentprediction and posttreatmentevaluationof outcomeafter definitive irradiation for prostatecancer.Int. J. Radiat.Oncol. Biol. Phys.32:307316; 1995. 12. Peschel,R. E. Prostate-specificantigen: Clinical versus pathologicalstage.Int. J. Radiat.Oncol. Biol. Phys. 30:493494; 1994. 13. Peschel,R. E.; Wilson,L.; Haffty, B.; Papadopoulis, D.; Rosenzweig,K.; Feltes,M. The effect of advancedageon the efficacy of radiation therapy for early breastcancer,local prostatecancerandgradeIII-IV gliomas.Int. J. Radiat.Oncol. Biol. Phys. 261539-544;1993. 14. Pollack,A.; Zagars,G. K.; Starkschall,G.; Childress,C. H.; Kopplin, S.; Boyer, A. L.; Rosen,I. I. Conventionalvs. conformal radiotherapyfor prostatecancer:Preliminaryresults of dosimetryand acute toxicity. Int. J. Radiat.Oncol. Biol. Phys.34:555-564; 1996. 15. Rosenzweig,K. E.; Morgan, W. R.; Lytton, B.; Peschel, R. E. Prostatespecificantigen following radiotherapyfor local prostatecancer.J. Urol. 153:1561-1564;1995.
PSA following RT 0 R. E. 16. Russell, K. J.; Caplan, R. J.; Laramore, G. E.; Bumison, C. M.; Maor, M. H.; Taylor, M. E.; Zink, S.; Davis, L. W.; Griffin, T. W. Photons vs. fast neutron external beam radiotherapy in the treatment of locally advanced prostate cancer: Results of a randomized prospective trial. Int. J. Radiat. Oncol. Biol. Phys. 28:47-54; 1994. 17. Schellhammer, P. F.; El-Mahdi, A. M.; Wright, G. L.; Kolm, P.; Ragle, R. Prostate-specific antigen to determine progression-free survival after radiation therapy for localized carcinoma of prostate. Urol. 42:13-19; 1993. 18. Shipley, W. U.; Verhey, L. J.; Munzenrider, J. E.; Suit, H. D.; Urie, M. M.; McManus, P. L.; Young, R. H.; Shipley, J. W.; Zietman, A. L.; Biggs, B. J.; Heney, N. M.; Gottein, M. Advanced prostate cancer: The results of a randomized comparative trial of high dose irradiation boosting with con-
PESCHEL
751
formal protons compared with conventional dose irradiation using photons alone. Int. J. Radiat. Oncol. Biol. Phys. 32:312; 1995. 19. Stein, A.; DeKernion, J. B.; Smith, R. B.; Dorey, F.; Patel, H. Prostate specific antigen levels after radical prostatectomy in patients with organ confined and locally extensive prostate cancer. J. Urol. 147:942-946; 1992. 20. Wilson, L. D.; Ennis, R.; Percarpio, B.; Peschel, R. E. Location of the prostatic apex and its relationship to the ischial tuberosities. Int. J. Radiat. Oncol. Biol. Phys. 29: 1133-l 138; 1994. 21. Zagars, G. K.; Pollack, A.; Kavadi, V. S.; von Eshenbach, A. C. Prostate-specific antigen and radiation therapy for clinically localized prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 32:293-306; 1995.