EDITORIAL COMMENT
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cancer. They clearly demonstrated that patients receiving brachy- therapy plus external radiotherapy performed worse in all quality of life domains, including sexual function and bothersomeness, and bowel function and bothersomeness, than those who received only external radiotherapy. Furthermore, combined treatment impacted more on a number of quality of life domains than radical prostatec- tomy. A large prospective study is in progress. Based on past data the impact of combined therapy would make it a much less desirable treatment method for patients with localized prostate cancer. It is well known that the higher the radiation dose, the greater the local control but the price is probably not worth the benefit. Jean B. deKernion Department of Urology University of California Los Angeles School of Medicine Los Angeles, California 1. Brandeis, J. M., Litwin, M. S., Burnison, C. M. et al: Quality of life outcomes after brachytherapy for early stage prostate can- cer. J Urol, 163: 851, 2000 Brachytherapy is now a widely accepted standard of care for pa- tients with clinically localized prostate cancer. This minimally inva- sive surgical procedure delivers about twice the radiation to the prostate gland compared to external beam therapy, while doing little or no harm to adjacent healthy tissue. The authors make a compel- ling argument for treating clinically localized prostate cancer with combined brachytherapy and external beam irradiation, and they demonstrate excellent long-term disease-free survival. Conceptually the idea of simultaneous irradiation is straightfor- ward and appealing. The brachytherapy application aims to achieve an even distribution of the energy sources, allowing the safe delivery of a tumor killing dose to the prostate and a narrow margin of surrounding tissue. The rationale for the external beam addition, no doubt influenced by the frequent up staging of clinical to pathological stage, is to sterilize potential pelvic micrometastasis. I would like to focus on outcome evaluation and cost. A major imped- iment to the scientific assessment of outcome results across different treatment barriers continues to be the lack of data from randomized clinical trials. In the absence of such standards serum PSA end points have come to have an enabling surrogate role by providing a framework for more objective comparisons of management strategies. It was gen- erally agreed that increasing PSA after treatment signified biochemical relapse and was an accurate assessment of disease recurrence but it proved difficult to arrive at a definitive PSA level denoting failure. To this end in 1996 ASTRO developed a consensus statement that pro- vided guidelines on the treatment of PSA only recurrence after external beam therapy, that is 3 consecutive PSA increases after treatment. This guideline is increasingly accepted and it appears to prove clinically meaningful. It allows the evaluation of patient response by more true- to-life trend analysis rather than a 1-time snapshot based on a solitary PSA value exceeding an arbitrarily selected level. For a recent update of our brachytherapy patient population that provides 12-year results using the ASTRO criteria for PSA failure after radiotherapy we com- pared results using a PSA threshold of 0.5 ng./ml. and the ASTRO definition. There was no significant difference in the 2 guidelines. Also, an in vivo prostate still has nonmalignant cells that may produce some PSA at least for a few years after treatment, and there are no organ systems in the human body in which therapeutic doses of radiation intentionally kill all of the cells in the treated area. If such an event occurred, radiation side effects would prohibit its use. Perhaps of greater concern in this cost conscious era in which many patients are treated according to health management organization guidelines is the additional expense incurred by treating all with com- bined brachytherapy and external beam irradiation, particularly when substantial evidence points to an increase in pathologically organ con- fined and margin-negative disease. At our institution the added cost for 5 weeks of external beam therapy amounts to $8,300. Some of our studies make a strong argument for managing low risk prostate cancer by an implant only. For example, using the ASTRO definition of failure we treated 510 low risk patients with a 125 I or 103 palladium ( 103 Pd) implant only between January 1, 1987 and Janu- ary 1, 1997. Median followup was 75 months (range 24 to 149), and disease-free survival at 3, 5 and 10 years with a median PSA of 0.2 ng./ml. was 89%, 85% and 83%, respectively (fig. 1). These monotherapy results are comparable to the combination therapy results reported by Critz et al but without additional cost and inconvenience for the patient. Another 233 high risk patients were treated with 45 Gy. external beam irradiation followed by an implant during the same period. Median followup was 64 months (range 24 to 141), and disease-free survival at 3, 5 and 10 years with a median PSA of 0.1 ng./ml. was 85%, 82% and 79%, respectively (fig. 2). Final judgment awaits the results of others treating clinically organ confined disease with brachytherapy. The surgical end point used by Critz et al may prove to be a yardstick that is too discrimi- nating to measure biochemical disease-free survival after radiation therapy. In conclusion, the report of the authors continues to pro- mote and validate prostate brachytherapy as an optimal treatment for early prostate cancer. Haakon Ragde Prostate Brachytherapy Northwest Hospital Seattle, Washington REPLY BY AUTHORS We believe that most of the comments about our manuscript high- light a major problem in localized prostate cancer clinical research, that is the lack of a standard definition for disease freedom. In this study we define disease freedom by PSA cutpoint 0.2 ng./ml., which is the identical definition used in some radical prostatectomy studies (reference 14 in article) 1 and a definition that produces significantly different results from the ASTRO definition of disease freedom (ref- erence 8 in article) commonly used by radiation investigators. The ASTRO definition of disease freedom is flawed. It requires 3 consecutive PSA increases 6 months apart above whatever nadir is achieved for recurrence (the key word is consecutive) but men are disease-free if an increasing PSA is fluctuating up and down. For FIG. 1. Biochemical disease-free survival and patients at risk af- ter 103 Pd or 125 I brachytherapy only. FIG. 2. Biochemical disease-free survival and patients at risk af- ter 45 Gy. external beam radiotherapy (XRT) plus 103 Pd or 125 I brachytherapy. SIMULTANEOUS IRRADIATION FOR PROSTATE CANCER 742
Transcript of EDITORIAL COMMENT
cancer. They clearly demonstrated that patients receiving brachy-therapy plus external radiotherapy performed worse in all quality oflife domains, including sexual function and bothersomeness, andbowel function and bothersomeness, than those who received onlyexternal radiotherapy. Furthermore, combined treatment impactedmore on a number of quality of life domains than radical prostatec-tomy. A large prospective study is in progress. Based on past data theimpact of combined therapy would make it a much less desirabletreatment method for patients with localized prostate cancer. It iswell known that the higher the radiation dose, the greater the localcontrol but the price is probably not worth the benefit.
Jean B. deKernionDepartment of UrologyUniversity of California Los Angeles School of MedicineLos Angeles, California
1. Brandeis, J. M., Litwin, M. S., Burnison, C. M. et al: Quality oflife outcomes after brachytherapy for early stage prostate can-cer. J Urol, 163: 851, 2000
Brachytherapy is now a widely accepted standard of care for pa-tients with clinically localized prostate cancer. This minimally inva-sive surgical procedure delivers about twice the radiation to theprostate gland compared to external beam therapy, while doing littleor no harm to adjacent healthy tissue. The authors make a compel-ling argument for treating clinically localized prostate cancer withcombined brachytherapy and external beam irradiation, and theydemonstrate excellent long-term disease-free survival.
Conceptually the idea of simultaneous irradiation is straightfor-ward and appealing. The brachytherapy application aims to achievean even distribution of the energy sources, allowing the safe deliveryof a tumor killing dose to the prostate and a narrow margin ofsurrounding tissue. The rationale for the external beam addition, nodoubt influenced by the frequent up staging of clinical to pathologicalstage, is to sterilize potential pelvic micrometastasis.
I would like to focus on outcome evaluation and cost. A major imped-iment to the scientific assessment of outcome results across differenttreatment barriers continues to be the lack of data from randomizedclinical trials. In the absence of such standards serum PSA end pointshave come to have an enabling surrogate role by providing a frameworkfor more objective comparisons of management strategies. It was gen-erally agreed that increasing PSA after treatment signified biochemicalrelapse and was an accurate assessment of disease recurrence but itproved difficult to arrive at a definitive PSA level denoting failure. Tothis end in 1996 ASTRO developed a consensus statement that pro-vided guidelines on the treatment of PSA only recurrence after externalbeam therapy, that is 3 consecutive PSA increases after treatment. Thisguideline is increasingly accepted and it appears to prove clinicallymeaningful. It allows the evaluation of patient response by more true-to-life trend analysis rather than a 1-time snapshot based on a solitaryPSA value exceeding an arbitrarily selected level. For a recent update ofour brachytherapy patient population that provides 12-year resultsusing the ASTRO criteria for PSA failure after radiotherapy we com-pared results using a PSA threshold of 0.5 ng./ml. and the ASTROdefinition. There was no significant difference in the 2 guidelines. Also,an in vivo prostate still has nonmalignant cells that may produce somePSA at least for a few years after treatment, and there are no organsystems in the human body in which therapeutic doses of radiationintentionally kill all of the cells in the treated area. If such an eventoccurred, radiation side effects would prohibit its use.
Perhaps of greater concern in this cost conscious era in which manypatients are treated according to health management organizationguidelines is the additional expense incurred by treating all with com-bined brachytherapy and external beam irradiation, particularly whensubstantial evidence points to an increase in pathologically organ con-fined and margin-negative disease. At our institution the added cost for5 weeks of external beam therapy amounts to $8,300.
Some of our studies make a strong argument for managing low riskprostate cancer by an implant only. For example, using the ASTROdefinition of failure we treated 510 low risk patients with a 125I or103palladium (103Pd) implant only between January 1, 1987 and Janu-ary 1, 1997. Median followup was 75 months (range 24 to 149), anddisease-free survival at 3, 5 and 10 years with a median PSA of 0.2ng./ml. was 89%, 85% and 83%, respectively (fig. 1). These monotherapyresults are comparable to the combination therapy results reported byCritz et al but without additional cost and inconvenience for the patient.Another 233 high risk patients were treated with 45 Gy. external beamirradiation followed by an implant during the same period. Median
followup was 64 months (range 24 to 141), and disease-free survival at3, 5 and 10 years with a median PSA of 0.1 ng./ml. was 85%, 82% and79%, respectively (fig. 2).
Final judgment awaits the results of others treating clinicallyorgan confined disease with brachytherapy. The surgical end pointused by Critz et al may prove to be a yardstick that is too discrimi-nating to measure biochemical disease-free survival after radiationtherapy. In conclusion, the report of the authors continues to pro-mote and validate prostate brachytherapy as an optimal treatmentfor early prostate cancer.
Haakon RagdeProstate BrachytherapyNorthwest HospitalSeattle, Washington
REPLY BY AUTHORS
We believe that most of the comments about our manuscript high-light a major problem in localized prostate cancer clinical research,that is the lack of a standard definition for disease freedom. In thisstudy we define disease freedom by PSA cutpoint 0.2 ng./ml., whichis the identical definition used in some radical prostatectomy studies(reference 14 in article)1 and a definition that produces significantlydifferent results from the ASTRO definition of disease freedom (ref-erence 8 in article) commonly used by radiation investigators.
The ASTRO definition of disease freedom is flawed. It requires 3consecutive PSA increases 6 months apart above whatever nadir isachieved for recurrence (the key word is consecutive) but men aredisease-free if an increasing PSA is fluctuating up and down. For
FIG. 1. Biochemical disease-free survival and patients at risk af-ter 103Pd or 125I brachytherapy only.
FIG. 2. Biochemical disease-free survival and patients at risk af-ter 45 Gy. external beam radiotherapy (XRT) plus 103Pd or 125Ibrachytherapy.
SIMULTANEOUS IRRADIATION FOR PROSTATE CANCER742
