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LETTERS TO THE EDITOR these approaches are relative survival rates, which require all cause mortality data for the case series as well as for a noncancer or general population standard, and competing risk life tables, which require cause specific mortality data for the case series. The multivariable cause specific survival analysis model used by Albertsen et al, although more sophisticated, is conceptually similar to these approaches in that it assumes the risk of death from competing causes (in this scenario prostate cancer and co-morbid disease) is independent. Consequently, interpretation of the interesting finding that co-morbidity is associated with prostate cancer specific mortality is difficult, since the estimates on which this conclusion are based come from a statistical approach that in essence assumes that there is no such association. Even if this conceptual inconsistency between the method and the conclusion proves inconsequential, and a statistical association between prostate cancer mortality and co-morbidity does indeed exist, stratification of prostate cancer mortality by co-morbidity may not rectify the potentially serious problems that can arise in a case series study. Albertsen e t a1 allude to problems in assignment of cause of death when they suggest that the observed association between prostate cancer mortality and co-morbidity could, in fact, result from errors, presumably these being that cases with co-morbidity may be less likely than cases without co-morbidity to be labeled as prostate cancer deaths regardless of whether cancer was causally linked to mortality. However, it is plausible that this type of error, if present, would occur differentially with respect to treatment type. Deaths among patients with co-morbidity who were more aggressively treated may be even less likely to be considered due to prostate cancer than those conservatively treated. Under these circumstances the stratified relative risk estimates would still be biased. Given these issues, it seems that a remaining challenge in using case series data to compare mortality experience of groups of prostate cancer patients goes beyond co-morbidity stratification, and lies in perfecting methods that are free from assumptions of competing risk independence and that do not rely on specific cause of death data. Respectfully, Craig J . Newschaffer Department of Medicine Thomas Jefferson University Jefferson Medical College 1025 Walnut St., Suite 119 Philadelphia, Pennsylvania 19107-5083
be unable to measure and model the true impact of treatment for prostate cancer among different patient populations.
RE: RANDOMIZED, PROSPECTIVE, CONTROLLED STUDY COMPARING RADICAL PROSTATECTOMY ALONE AND NEOADJUVANT ANDROGEN WITHDRAWAL IN THE TREATMENT OF LOCALIZED PROSTATE CANCER
S. L. Goldenberg, L. H. Klotz, J . Srigley. M . A. S. Jewett, D. Mador, Y. Fradet, J . Barkin, J . Chin, J.-M. Paguin, M . J . Bullock, S. LaPlante and Canadian Urologic Oncology Group J . Urol., 168: 873-877, 1996
To the Editor. I always look to the lead article in the Journal as being exemplary of the cutting edge of science in our field. In the lead article in the September issue on neoadjuvant hormonal therapy prior to radical prostatectomy, the authors note a striking 37% reduction in positive surgical margin in those patients who received treatment with cyproterone acetate for 3 months before surgery. The major factor responsible for this reduction was an increase in the number of patients who had organ confined disease. In the patients undergoing surgery only 20% had organ confined disease, whereas in patients who received cyproterone acetate the disease was organ confined in 42%. Indeed, even 2 of the 7 cases with positive nodes were converted to organ confined status. Unfortunately, in the discussion the authors do not explain how this occurred. Respectfully, Patrick C. Walsh James Buchannn Brady Urnlogical Institute Johns Hopkins Hospital Baltimore, Maryland 21287-2101
Reply by Authors. In scientific research one formulates a hypothesis and tests it with an appropriately designed and conducted trial. We addressed the hypothesis that 3 months of neoadjuvant androgen withdrawal therapy would alter the pathological staging of clinically localized cancer of the prostate. We found an increase in specimen confined tumors and a decrease in positive margins. As is clearly 1. Rothman, K.: Modem Epidemiology. Boston: Little, Brown & explained in the Results, a tumor may be classified as pathological Co., 1986. T2 with a positive margin if the capsule, lymph nodes and seminal vesicles are not involved. The 2 patients who had positive nodes with an organ confined primary were not included in the overall organ confined group. This is clearly shown in table 5. Reply by Authors. The purpose of our report was to explore the We are describing a simple process. Androgen withdrawal results relationship between competing medical risks and all cause mortalin cell death via apoptosis whether the cells lie inside or outside the ity among a group of men 65 to 75 years old a t diagnosis, the age capsule of the prostate. The reduction in positive margins may simrange in which most men are diagnosed with this disease. Many ply be due to a smaller prostate and a smaller cancer in the neoadrecent case series analyses rely on cause specific survival as the juvant group with surgical margins and, therefore, a wider relative definitive outcome metric. While this measure may highlight the to a smaller gland. Also, margins may be decreased if apoptosis and impact of treatment, it effectively ignores the impact of competing cell death occur preferentially a t the periphery of the tumor as has risks. These risks lower the relative impact of treatment, particu- been observed in other systemically treated solid malignancies. larly among the elderly and, therefore, must be incorporated in any These mechanisms would explain our observations. decision analysis by older men who face difficult decisions regarding treatment. We agree with Newschaffer that we need to go beyond co-morbidity stratification when comparing case series data but this requires the systematic identification of other statistically significant confoundRE: POSTOPERATIVE RADIOTHERAPY FOR STAGE pT3 ing factors that impact all cause survival. We also agree that we CARCINOMA OF THE PROSTATE: IMPROVED LOCAL must move beyond cause specific survival analyses because of the CONTROL many problems associated with ascertaining cause of death. UnforI. Syndikus, T. Pickles, E. Kostashuk and L. D. Sullivan tunately, even if we can develop tools to adjust for these confounding variables, doubts will linger concerning case series data analysis J. Urol., 155: 1983-1986, 1996 because of the potential bias introduced by an unidentified confoundTo the Editor. The authors presented results of 203 patients with ing variable. Randomized trials are the ideal way to adjust for many of these biases but are extraordinarily difficult to conduct for this clinical stage T2 prostate carcinomas who had undergone radical prostatectomy, followed by early radiotherapy in some cases and by disease. In the absence of data from randomized trials, researchers must radiotherapy for histologically proved local recurrence in others. continue to search for variables that impact all cause survival SO that Their analysis is based on 123 patients with postoperative stage the extent of their effect can be estimated. We already know of many, pT3NONx tumors and 80 of 123 treated with early radiotherapy including tumor stage and grade and the treatment offered. Our following radical prostatectomy. They demonstrated a significant report documented the importance of measuring competing risks, increase in the local control rate for patients treated with early while other researchers are investigating the impact of social sup- radiotherapy (p = 0.005). However, the rate of metastases and the Port systems and marital status. Until the impact of these potential cause specific survival rates did not differ significantly. Additionally, confounding variables can be estimated accurately, researchers will a higher rate of severe (Radiation Therapy Oncology Group m d e IW
LETTERS TO THE EDITOR these approaches are relative survival rates, which require all cause mortality data for the case series as well as for a noncancer or general population standard, and competing risk life tables, which require cause specific mortality data for the case series. The multivariable cause specific survival analysis model used by Albertsen et al, although more sophisticated, is conceptually similar to these approaches in that it assumes the risk of death from competing causes (in this scenario prostate cancer and co-morbid disease) is independent. Consequently, interpretation of the interesting finding that co-morbidity is associated with prostate cancer specific mortality is difficult, since the estimates on which this conclusion are based come from a statistical approach that in essence assumes that there is no such association. Even if this conceptual inconsistency between the method and the conclusion proves inconsequential, and a statistical association between prostate cancer mortality and co-morbidity does indeed exist, stratification of prostate cancer mortality by co-morbidity may not rectify the potentially serious problems that can arise in a case series study. Albertsen e t a1 allude to problems in assignment of cause of death when they suggest that the observed association between prostate cancer mortality and co-morbidity could, in fact, result from errors, presumably these being that cases with co-morbidity may be less likely than cases without co-morbidity to be labeled as prostate cancer deaths regardless of whether cancer was causally linked to mortality. However, it is plausible that this type of error, if present, would occur differentially with respect to treatment type. Deaths among patients with co-morbidity who were more aggressively treated may be even less likely to be considered due to prostate cancer than those conservatively treated. Under these circumstances the stratified relative risk estimates would still be biased. Given these issues, it seems that a remaining challenge in using case series data to compare mortality experience of groups of prostate cancer patients goes beyond co-morbidity stratification, and lies in perfecting methods that are free from assumptions of competing risk independence and that do not rely on specific cause of death data. Respectfully, Craig J . Newschaffer Department of Medicine Thomas Jefferson University Jefferson Medical College 1025 Walnut St., Suite 119 Philadelphia, Pennsylvania 19107-5083
be unable to measure and model the true impact of treatment for prostate cancer among different patient populations.
RE: RANDOMIZED, PROSPECTIVE, CONTROLLED STUDY COMPARING RADICAL PROSTATECTOMY ALONE AND NEOADJUVANT ANDROGEN WITHDRAWAL IN THE TREATMENT OF LOCALIZED PROSTATE CANCER
S. L. Goldenberg, L. H. Klotz, J . Srigley. M . A. S. Jewett, D. Mador, Y. Fradet, J . Barkin, J . Chin, J.-M. Paguin, M . J . Bullock, S. LaPlante and Canadian Urologic Oncology Group J . Urol., 168: 873-877, 1996
To the Editor. I always look to the lead article in the Journal as being exemplary of the cutting edge of science in our field. In the lead article in the September issue on neoadjuvant hormonal therapy prior to radical prostatectomy, the authors note a striking 37% reduction in positive surgical margin in those patients who received treatment with cyproterone acetate for 3 months before surgery. The major factor responsible for this reduction was an increase in the number of patients who had organ confined disease. In the patients undergoing surgery only 20% had organ confined disease, whereas in patients who received cyproterone acetate the disease was organ confined in 42%. Indeed, even 2 of the 7 cases with positive nodes were converted to organ confined status. Unfortunately, in the discussion the authors do not explain how this occurred. Respectfully, Patrick C. Walsh James Buchannn Brady Urnlogical Institute Johns Hopkins Hospital Baltimore, Maryland 21287-2101
Reply by Authors. In scientific research one formulates a hypothesis and tests it with an appropriately designed and conducted trial. We addressed the hypothesis that 3 months of neoadjuvant androgen withdrawal therapy would alter the pathological staging of clinically localized cancer of the prostate. We found an increase in specimen confined tumors and a decrease in positive margins. As is clearly 1. Rothman, K.: Modem Epidemiology. Boston: Little, Brown & explained in the Results, a tumor may be classified as pathological Co., 1986. T2 with a positive margin if the capsule, lymph nodes and seminal vesicles are not involved. The 2 patients who had positive nodes with an organ confined primary were not included in the overall organ confined group. This is clearly shown in table 5. Reply by Authors. The purpose of our report was to explore the We are describing a simple process. Androgen withdrawal results relationship between competing medical risks and all cause mortalin cell death via apoptosis whether the cells lie inside or outside the ity among a group of men 65 to 75 years old a t diagnosis, the age capsule of the prostate. The reduction in positive margins may simrange in which most men are diagnosed with this disease. Many ply be due to a smaller prostate and a smaller cancer in the neoadrecent case series analyses rely on cause specific survival as the juvant group with surgical margins and, therefore, a wider relative definitive outcome metric. While this measure may highlight the to a smaller gland. Also, margins may be decreased if apoptosis and impact of treatment, it effectively ignores the impact of competing cell death occur preferentially a t the periphery of the tumor as has risks. These risks lower the relative impact of treatment, particu- been observed in other systemically treated solid malignancies. larly among the elderly and, therefore, must be incorporated in any These mechanisms would explain our observations. decision analysis by older men who face difficult decisions regarding treatment. We agree with Newschaffer that we need to go beyond co-morbidity stratification when comparing case series data but this requires the systematic identification of other statistically significant confoundRE: POSTOPERATIVE RADIOTHERAPY FOR STAGE pT3 ing factors that impact all cause survival. We also agree that we CARCINOMA OF THE PROSTATE: IMPROVED LOCAL must move beyond cause specific survival analyses because of the CONTROL many problems associated with ascertaining cause of death. UnforI. Syndikus, T. Pickles, E. Kostashuk and L. D. Sullivan tunately, even if we can develop tools to adjust for these confounding variables, doubts will linger concerning case series data analysis J. Urol., 155: 1983-1986, 1996 because of the potential bias introduced by an unidentified confoundTo the Editor. The authors presented results of 203 patients with ing variable. Randomized trials are the ideal way to adjust for many of these biases but are extraordinarily difficult to conduct for this clinical stage T2 prostate carcinomas who had undergone radical prostatectomy, followed by early radiotherapy in some cases and by disease. In the absence of data from randomized trials, researchers must radiotherapy for histologically proved local recurrence in others. continue to search for variables that impact all cause survival SO that Their analysis is based on 123 patients with postoperative stage the extent of their effect can be estimated. We already know of many, pT3NONx tumors and 80 of 123 treated with early radiotherapy including tumor stage and grade and the treatment offered. Our following radical prostatectomy. They demonstrated a significant report documented the importance of measuring competing risks, increase in the local control rate for patients treated with early while other researchers are investigating the impact of social sup- radiotherapy (p = 0.005). However, the rate of metastases and the Port systems and marital status. Until the impact of these potential cause specific survival rates did not differ significantly. Additionally, confounding variables can be estimated accurately, researchers will a higher rate of severe (Radiation Therapy Oncology Group m d e IW