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Radiation Therapy
0022-5347 /92/14 73-0929$03.00 /0 VoL 147, 929-930, March 1992
THE JOURNAL OF UROLOGY
Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, !NC.
Printed in U.S.A.
Editorial RADIATION THERAPY The article by Kaplan et al (page 917) gives us significant and interesting new information correlating the important treatment outcome variables of overall survival and disease or cause specific survival with intermediate outcome variablespost-irradiation clinical local control and prostate re-biopsy findings in patients with clinical local control and an elevated serum prostate specific antigen (PSA). The power or significance of the study results from the premier status of their department in the treatment of patients with prostate cancer, the thoroughness and length of patient followup (unsurpassed by any other publication) and the thoroughness of the statistical analysis. Although table 1 in the article attempts to minimize confusing the reader, one should be alerted to the uniqueness of the Stanford staging system. Stanford stage Tl is synonymous with stage T2 in the International Union Against Cancer system, stage Bin the Jewett system and stage TBNX in the Prostate Organ System Program staging classification of Whitmore et al. 1 Stanford stages T2 and T3 would probably be stage T3 by the International Union Against Cancer stage C by the Jewett system and stage TcNx by the Prostate Organ System Program/Whitmore system. 1 Based on their thorough analysis the authors conclude that the ability to achieve clinical local control after radiotherapy is stage (or initial tumor volume) dependent with a rate at 15 years of 78% for Stanford stage Tl, 61 % for T2 and 65% for stage T3. They also conclude that those patients who achieve clinical local control have an improved disease or cancer specific survival but no difference in overall survival. The reason for as yet no perceived benefit in overall survival is unclear but may yield to further subgroup analysis of this large patient population. I look forward to the authors analyzing these data further for possible covarying parameters of tumor heterogeneity and/ or confounding factors not yet presented, such as tumor histology, tumor deoxyribonucleic acid (DNA) content, patient age or, if available, lymph nodal status. Either subgroup or multivariate analysis of these factors could help sort out or test some possible explanations of these data. For instance, the association of a local tumor regrowth following irradiation with a decrease in cancer specific survival but not in overall survival could be explained if certain tumor subgroups (such as those of poor differentiation or with aneuploid DNA content) were resistant to radiotherapy and androgen ablation or it could be explained if radiosensitivity and sensitivity to androgen ablation were higher in the older population who die more rapidly of intercurrent illnesses. Thus, the authors should be encouraged to perform subgroup or multivariate analysis and attempt to identify certain subgroups whose tumor control following radiation therapy correlates with overall survival and also disease-free survival. The authors also conclude that the significance of a positive prostate re-biopsy after radiotherapy in the absence of a clinically detectable recurrence is unclear. However in the Stanford stage Tl (a nodular tumor limited to the prostate gland) their data showed a significant decrease in disease specific survival in those patients with clinical local control, an elevated PSA and a positive re-biopsy. This suggests that patients with a positive prostate re-biopsy and an elevated PSA represent an important group to study further by further subgroup and multivariate analysis, and also by treatment at the time of finding an elevated PSA and a positive prostate re-biopsy. The authors found a high incidence of positive prostate re-biopsies 929
because of their method of selecting the men to be re-biopsiedthose with an elevated serum PSA. In a group of International Union Against Cancer stage T3 cases (similar to the combined T2 and T3 cases in the Stanford system) that we re-biopsied after irradiation on a protocol of 68 or 75.5 Gy. we noted a significant correlation between the positive rate and the current PSA level at the time of re-biopsy. Of those patients with a PSA level greater than normal 71 % were found to have a positive re-biopsy, whereas those with a normal serum PSA at the time of re-biopsy only had a significantly lower (p <0.02) re-biopsy positive rate of 21 %. 2 Thus, the observed high rate of positive prostate re-biopsies should not be extrapolated to an unselected series of patients treated by radiation therapy because, as these authors clearly state, these patients were selected for biopsy because they had an elevated PSA. In our series and that of Marinelli et al (page 922) the overall positive prostate re-biopsy rate was significantly lower (38% and 22%, respectively). The article by Martinelli et al is a concise description of their experience with prostate re-biopsy following 192 iridium (3,500 cGy. or rad) interstitial boost irradiation to the prostate combined with external beam irradiation (4,000 to 5,000 cGy. or rad). The biological effect of this higher dose in a shorter overall time appears greater as their rate of re-biopsy positivity is relatively low at 22%. They report a correlation with the rate of re-biopsy positivity and the increasing tumor size (stage) as well as loss of histological differentiation. Their technique has recently improved such that a previously reported high rate of anal/rectal complications has been sharply reduced by differential loading of the radioactive sources so that the anterior rectal wall is not irradiated to excessive dose. This approach along with one ongoing at Stanford, which is similar except that it adds interstitial hyperthermia to the 192iridium implant, offer encouragement that higher radiation doses can be delivered safely to the prostate target volume with a possible increase in local success. However, any benefit from a new treatment regimen will require confirmation by a phase III randomized trial assessing outcome compared to standard approaches. Finally, I must caution the readership that the study by Moreno and Ahlering (page 926) may be a flawed sample and an inaccurate representation of the frequency of late complications. While the title suggests an attempt to analyze radiation complications in all patients radiated for prostate adenocarcinoma, this is not the focus of the report. The authors identified retrospectively from their tumor registry 33 patients who, having initially received definitive radiotherapy somewhere, died at their institution of prostate cancer during an 11-year period. They then take 33 as the denominator for all such treated patients when the irradiated population is likely at least 10 times this number. Their tumor registry search identified 23 patients dying of prostate cancer at their institutions who had sustained local pelvic complications from radiation (or local tumor regrowth). Because the tumor registry only contained 33 irradiated patients who died of prostate cancer, they conclude that the rate of significant complications following irradiation is 23 of 33 or 70% in this subgroup subsequently dying of disseminated cancer. When using the compromised technique of a retrospective chart review to determine an incidence rate, the authors are obliged to make every effort to identify or at least estimate the denominator of the total population base and of this subset of patients. Since this tumor registry may well
930
SHIPLEY
All Complications Complications of Moderate Severity 30
All Ano-rectal and Urinary Complications 20
10
.... - . . --- ...
,...,.
. -----"'
o·-+"'"'-'-~---.---~--.--~--.--~-.--.--.----. 2
0
3
6
4
--Years After XRT-End FIG. 1. Actuarial incidence of complication as function of time after irradiation (XRT). Reprinted with permission. 3 100
~
75
0
~ u
it:> 0
u
Q'.
50
0
;;, :>
COMPLICATION/TOTAL
"
~
"•
(21/193) 25
11,
0
13
69
J.9,34
0
10
5
YEARS FROM ONSTUDY
FIG. 2. Actuarial incidence of moderate or major complications as function of time following radiation therapy in subset of 193 patients subsequently dying of prostate cancer either as primary or secondary cause in series reported by Lawton et al4 (personal communication from Dr. James Cox, Chairman, Radiation Therapy Oncology Group). GU/GI, genitourinary /gastrointestinal.
Moderate and major urinary and intestinal complications by patient groups Pt. Group All evaluable Distant metastases Distant metastases and death from prostate Ca Death from prostate Ca
Total Total No. Grade 3 Grade 4 Grade 5 Complcations Evaluated No.(%) No.(%) No.(%) No.(%) 2 (0.2) 0 (0.0)
106 (10.4) 36 (9.7)
186
14 (7.5)
5 (2.7) 0 (0,0)
19 (10.2)
193
16 (8.3)
5 (2.6) 0 (0.0)
21 (10.9)
1,020 372
89 (8.7) 15 (1.5) 28 (7.5) 8 (2.2)
are urinary complications. 3 This graph represents data from a prospective analysis of 289 patients with followup on all patients who were treated for a 5-year period at that institution beginning January 1, 1984. This level of complications is consistent with that reported recently by the Radiation Therapy Oncology Group (RTOG) in 1,020 irradiated patients evaluated prospectively on RTOG protocols from 1976 through 1983 with a minimum followup in surviving patients of 7 years. A 3.3% incidence of intestinal complications of moderate severity or worse and a 7.7% incidence of urinary complications of moderate severity or worse were reported. The RTOG patients had a 1.1 % incidence of severe complications requiring major surgical intervention or prolonged hospitalization. In a further analysis of the RTOG population base of a subset 193 patients who died of prostate cancer a moderate or major urinary or intestinal complication following·wtliation ttrera:py developed in 21 (11 %) (table and fig. 2). 4 Thus, I judge that the true incidence of late local complications after radiotherapy in the subset of patients defined by Moreno and Ahlering (those dying with metastatic cancer after definitive radiotherapy) is truly in the range of 11 % rather than the 70% that they have found in the tumor registry. Their low incidence of pelvic complications (or tumor regrowth) in 54 men initially treated with androgen suppression for metastatic disease is interesting, and may only reflect a short-time bias (because of the more advanced metastatic disease at presentation, these patients do not live long enough to manifest local problems). However, being more optimistic, this favorable local result may add to the hopeful rationale that present day radiation therapy plus early hormone therapy may be superior to radiation alone in some subsets of patients without known metastases. This possibility is being evaluated now by randomized phase III trials by the RTOG and in Europe. A more balanced presentation of the single institution data by Moreno and Ahlering would have resulted if the retrospective report had been a combined effort of the Departments of Radiation Oncology and Urology. William U. Shipley Genito- Urinary Radiation Oncology Unit Department of Radiation Oncology Massachusetts General Hospital Boston, Massachusetts REFERENCES
1. Whitmore, W. F., Jr., Catalona, W. J., Grayhack, J. T.: Prostate
be from a referral center for complicated cases, this population denominator is a difficult number to estimate but most likely it would be in excess of 300 or 400 patients. Thus, I think that their conclusions warrant caution and more attention to actual present day complication rates. Radiation oncologists, like urologists, have made major improvements in treatment administrations during the last decade leading to a reduction in morbidity from radical surgery and radical radiotherapy (fig. 1). Figure 1 from the M. D. Anderson Hospital series documents a cumulative risk of all complica tions as being 18% up to 5 years when the curves reach a plateau and a cumulative incidence of 7% of complications of moderate severity: 2% are anal/rectal complications and 5% 0
organ system program staging classification for prostate cancer. In: A Multidisciplinary Analysis of Controversies in the Management of Prostate Cancer. Edited by D. S. Coffey, M. I. Resnick, F. A. Dorr and J.P. Karr. New York: Plenum Press, pp. 295-297, 1988. 2. Dugan, T. C., Shipley, W. P., Young, R. H., Verhey, L. J., Althausen, A. F., Heney, N. M., McManus, P. L. and Abraham, E. H.: Biopsy after external beam radiation therapy for adenocarcinoma of the prostate: correlation with original histologic grade and current prostate specific antigen levels. J. Urol., 146: 1313, 1991.
3. Greskovich, F. J., Zagars, G. K., Sherman, N. E. and Johnson, D. E.: Complications following external beam radiation therapy for prostate cancer: an analysis of patients treated with and without staging pelvic lymphadenectomy. J. Urol., 146: 798, 1991. 4. Lawton, C. A., Won, M., Pilepich, M. V., Asbell, S. 0., Shipley, W. U., Hanks, G. E., Cox, J. D., Perez, C. A., Sause, W. T., Doggett, S. R. L. and Rubin, P.: Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostateanalysis of RTOG study 7506 and study 7706. Int. J. Rad. Oncol. Biol. Phys., 21: 935, 1991.
THE JOURNAL OF UROLOGY
Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, !NC.
Printed in U.S.A.
Editorial RADIATION THERAPY The article by Kaplan et al (page 917) gives us significant and interesting new information correlating the important treatment outcome variables of overall survival and disease or cause specific survival with intermediate outcome variablespost-irradiation clinical local control and prostate re-biopsy findings in patients with clinical local control and an elevated serum prostate specific antigen (PSA). The power or significance of the study results from the premier status of their department in the treatment of patients with prostate cancer, the thoroughness and length of patient followup (unsurpassed by any other publication) and the thoroughness of the statistical analysis. Although table 1 in the article attempts to minimize confusing the reader, one should be alerted to the uniqueness of the Stanford staging system. Stanford stage Tl is synonymous with stage T2 in the International Union Against Cancer system, stage Bin the Jewett system and stage TBNX in the Prostate Organ System Program staging classification of Whitmore et al. 1 Stanford stages T2 and T3 would probably be stage T3 by the International Union Against Cancer stage C by the Jewett system and stage TcNx by the Prostate Organ System Program/Whitmore system. 1 Based on their thorough analysis the authors conclude that the ability to achieve clinical local control after radiotherapy is stage (or initial tumor volume) dependent with a rate at 15 years of 78% for Stanford stage Tl, 61 % for T2 and 65% for stage T3. They also conclude that those patients who achieve clinical local control have an improved disease or cancer specific survival but no difference in overall survival. The reason for as yet no perceived benefit in overall survival is unclear but may yield to further subgroup analysis of this large patient population. I look forward to the authors analyzing these data further for possible covarying parameters of tumor heterogeneity and/ or confounding factors not yet presented, such as tumor histology, tumor deoxyribonucleic acid (DNA) content, patient age or, if available, lymph nodal status. Either subgroup or multivariate analysis of these factors could help sort out or test some possible explanations of these data. For instance, the association of a local tumor regrowth following irradiation with a decrease in cancer specific survival but not in overall survival could be explained if certain tumor subgroups (such as those of poor differentiation or with aneuploid DNA content) were resistant to radiotherapy and androgen ablation or it could be explained if radiosensitivity and sensitivity to androgen ablation were higher in the older population who die more rapidly of intercurrent illnesses. Thus, the authors should be encouraged to perform subgroup or multivariate analysis and attempt to identify certain subgroups whose tumor control following radiation therapy correlates with overall survival and also disease-free survival. The authors also conclude that the significance of a positive prostate re-biopsy after radiotherapy in the absence of a clinically detectable recurrence is unclear. However in the Stanford stage Tl (a nodular tumor limited to the prostate gland) their data showed a significant decrease in disease specific survival in those patients with clinical local control, an elevated PSA and a positive re-biopsy. This suggests that patients with a positive prostate re-biopsy and an elevated PSA represent an important group to study further by further subgroup and multivariate analysis, and also by treatment at the time of finding an elevated PSA and a positive prostate re-biopsy. The authors found a high incidence of positive prostate re-biopsies 929
because of their method of selecting the men to be re-biopsiedthose with an elevated serum PSA. In a group of International Union Against Cancer stage T3 cases (similar to the combined T2 and T3 cases in the Stanford system) that we re-biopsied after irradiation on a protocol of 68 or 75.5 Gy. we noted a significant correlation between the positive rate and the current PSA level at the time of re-biopsy. Of those patients with a PSA level greater than normal 71 % were found to have a positive re-biopsy, whereas those with a normal serum PSA at the time of re-biopsy only had a significantly lower (p <0.02) re-biopsy positive rate of 21 %. 2 Thus, the observed high rate of positive prostate re-biopsies should not be extrapolated to an unselected series of patients treated by radiation therapy because, as these authors clearly state, these patients were selected for biopsy because they had an elevated PSA. In our series and that of Marinelli et al (page 922) the overall positive prostate re-biopsy rate was significantly lower (38% and 22%, respectively). The article by Martinelli et al is a concise description of their experience with prostate re-biopsy following 192 iridium (3,500 cGy. or rad) interstitial boost irradiation to the prostate combined with external beam irradiation (4,000 to 5,000 cGy. or rad). The biological effect of this higher dose in a shorter overall time appears greater as their rate of re-biopsy positivity is relatively low at 22%. They report a correlation with the rate of re-biopsy positivity and the increasing tumor size (stage) as well as loss of histological differentiation. Their technique has recently improved such that a previously reported high rate of anal/rectal complications has been sharply reduced by differential loading of the radioactive sources so that the anterior rectal wall is not irradiated to excessive dose. This approach along with one ongoing at Stanford, which is similar except that it adds interstitial hyperthermia to the 192iridium implant, offer encouragement that higher radiation doses can be delivered safely to the prostate target volume with a possible increase in local success. However, any benefit from a new treatment regimen will require confirmation by a phase III randomized trial assessing outcome compared to standard approaches. Finally, I must caution the readership that the study by Moreno and Ahlering (page 926) may be a flawed sample and an inaccurate representation of the frequency of late complications. While the title suggests an attempt to analyze radiation complications in all patients radiated for prostate adenocarcinoma, this is not the focus of the report. The authors identified retrospectively from their tumor registry 33 patients who, having initially received definitive radiotherapy somewhere, died at their institution of prostate cancer during an 11-year period. They then take 33 as the denominator for all such treated patients when the irradiated population is likely at least 10 times this number. Their tumor registry search identified 23 patients dying of prostate cancer at their institutions who had sustained local pelvic complications from radiation (or local tumor regrowth). Because the tumor registry only contained 33 irradiated patients who died of prostate cancer, they conclude that the rate of significant complications following irradiation is 23 of 33 or 70% in this subgroup subsequently dying of disseminated cancer. When using the compromised technique of a retrospective chart review to determine an incidence rate, the authors are obliged to make every effort to identify or at least estimate the denominator of the total population base and of this subset of patients. Since this tumor registry may well
930
SHIPLEY
All Complications Complications of Moderate Severity 30
All Ano-rectal and Urinary Complications 20
10
.... - . . --- ...
,...,.
. -----"'
o·-+"'"'-'-~---.---~--.--~--.--~-.--.--.----. 2
0
3
6
4
--Years After XRT-End FIG. 1. Actuarial incidence of complication as function of time after irradiation (XRT). Reprinted with permission. 3 100
~
75
0
~ u
it:> 0
u
Q'.
50
0
;;, :>
COMPLICATION/TOTAL
"
~
"•
(21/193) 25
11,
0
13
69
J.9,34
0
10
5
YEARS FROM ONSTUDY
FIG. 2. Actuarial incidence of moderate or major complications as function of time following radiation therapy in subset of 193 patients subsequently dying of prostate cancer either as primary or secondary cause in series reported by Lawton et al4 (personal communication from Dr. James Cox, Chairman, Radiation Therapy Oncology Group). GU/GI, genitourinary /gastrointestinal.
Moderate and major urinary and intestinal complications by patient groups Pt. Group All evaluable Distant metastases Distant metastases and death from prostate Ca Death from prostate Ca
Total Total No. Grade 3 Grade 4 Grade 5 Complcations Evaluated No.(%) No.(%) No.(%) No.(%) 2 (0.2) 0 (0.0)
106 (10.4) 36 (9.7)
186
14 (7.5)
5 (2.7) 0 (0,0)
19 (10.2)
193
16 (8.3)
5 (2.6) 0 (0.0)
21 (10.9)
1,020 372
89 (8.7) 15 (1.5) 28 (7.5) 8 (2.2)
are urinary complications. 3 This graph represents data from a prospective analysis of 289 patients with followup on all patients who were treated for a 5-year period at that institution beginning January 1, 1984. This level of complications is consistent with that reported recently by the Radiation Therapy Oncology Group (RTOG) in 1,020 irradiated patients evaluated prospectively on RTOG protocols from 1976 through 1983 with a minimum followup in surviving patients of 7 years. A 3.3% incidence of intestinal complications of moderate severity or worse and a 7.7% incidence of urinary complications of moderate severity or worse were reported. The RTOG patients had a 1.1 % incidence of severe complications requiring major surgical intervention or prolonged hospitalization. In a further analysis of the RTOG population base of a subset 193 patients who died of prostate cancer a moderate or major urinary or intestinal complication following·wtliation ttrera:py developed in 21 (11 %) (table and fig. 2). 4 Thus, I judge that the true incidence of late local complications after radiotherapy in the subset of patients defined by Moreno and Ahlering (those dying with metastatic cancer after definitive radiotherapy) is truly in the range of 11 % rather than the 70% that they have found in the tumor registry. Their low incidence of pelvic complications (or tumor regrowth) in 54 men initially treated with androgen suppression for metastatic disease is interesting, and may only reflect a short-time bias (because of the more advanced metastatic disease at presentation, these patients do not live long enough to manifest local problems). However, being more optimistic, this favorable local result may add to the hopeful rationale that present day radiation therapy plus early hormone therapy may be superior to radiation alone in some subsets of patients without known metastases. This possibility is being evaluated now by randomized phase III trials by the RTOG and in Europe. A more balanced presentation of the single institution data by Moreno and Ahlering would have resulted if the retrospective report had been a combined effort of the Departments of Radiation Oncology and Urology. William U. Shipley Genito- Urinary Radiation Oncology Unit Department of Radiation Oncology Massachusetts General Hospital Boston, Massachusetts REFERENCES
1. Whitmore, W. F., Jr., Catalona, W. J., Grayhack, J. T.: Prostate
be from a referral center for complicated cases, this population denominator is a difficult number to estimate but most likely it would be in excess of 300 or 400 patients. Thus, I think that their conclusions warrant caution and more attention to actual present day complication rates. Radiation oncologists, like urologists, have made major improvements in treatment administrations during the last decade leading to a reduction in morbidity from radical surgery and radical radiotherapy (fig. 1). Figure 1 from the M. D. Anderson Hospital series documents a cumulative risk of all complica tions as being 18% up to 5 years when the curves reach a plateau and a cumulative incidence of 7% of complications of moderate severity: 2% are anal/rectal complications and 5% 0
organ system program staging classification for prostate cancer. In: A Multidisciplinary Analysis of Controversies in the Management of Prostate Cancer. Edited by D. S. Coffey, M. I. Resnick, F. A. Dorr and J.P. Karr. New York: Plenum Press, pp. 295-297, 1988. 2. Dugan, T. C., Shipley, W. P., Young, R. H., Verhey, L. J., Althausen, A. F., Heney, N. M., McManus, P. L. and Abraham, E. H.: Biopsy after external beam radiation therapy for adenocarcinoma of the prostate: correlation with original histologic grade and current prostate specific antigen levels. J. Urol., 146: 1313, 1991.
3. Greskovich, F. J., Zagars, G. K., Sherman, N. E. and Johnson, D. E.: Complications following external beam radiation therapy for prostate cancer: an analysis of patients treated with and without staging pelvic lymphadenectomy. J. Urol., 146: 798, 1991. 4. Lawton, C. A., Won, M., Pilepich, M. V., Asbell, S. 0., Shipley, W. U., Hanks, G. E., Cox, J. D., Perez, C. A., Sause, W. T., Doggett, S. R. L. and Rubin, P.: Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostateanalysis of RTOG study 7506 and study 7706. Int. J. Rad. Oncol. Biol. Phys., 21: 935, 1991.