Re: Intermediate-Term Survival Results in Clinically Understaged Prostate Cancer Patients Following Radical Prostatectomy, by W. J. Catalona, D. R. Miller and L. R. Kavoussi J. Urol., 140: 540-543, 1988

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well differentiated tumors is not as clear cut. The issue of our study is the prognostic value of the initial cytological grade (well and moderately well differentiated) in the followup of patients without metastases who were not treated actively initially. No difference was found between the 2 groups although this has been found in other studies, and we may need a larger material and longer observation time to detect this difference. 1. Esposti, P. L.: Cytologic malignancy grading of prostatic carcinoma by transrectal aspiration biopsy. A five-year follow-up study of 469 hormone-treated patients. Scand. J. Urol. Nephrol., 5: 199, 1971. RE: MANAGEMENT OF STAGE A PROSTATE CANCER WITH A HIGH PROBABILITY OF PROGRESSION

B. A. Lowe and M. B. Listrom J. Urol., 140: 1345-1347, 1988

To the Editor. The authors have put their unmatched, nonrandomized, retrospectively established, untreated control group at an unfair disadvantage compared to radiotherapy and surgical ablation groups. They report the results as "time to progression". Time to "progression is defined according to the aforementioned criteria". When the reader traces back in the text to find the definition of progression it reads, "progression was defined as the development of metastasis or symptomatic local recurrence". This is as close as one gets. One does not find out from the text what proportion of the 15 patients (among the control group of 33) had new metastases nor is the word symptomatic defined further. Was it complete urinary retention? Was it dysuria? Was it defined by a statistically significant decrease in the peak flow rate on multiple measurements? The inequity of the comparison is evident when one considers that in the surgical group the source of future urinary symptoms is gone, namely the primary site. Similarly, radiotherapy can be expected to diminish the vitality of the local cells. However, every second year medical student knows that this disease does not kill by local extension. The patient and the taxpayer want to know whether these therapies will prevent death of overwhelming metastases. The authors make no claim that 4 deaths among 33 controls are significantly different in a statistical sense from O deaths in the surgical group and 1 in the radiotherapy group. According to a nonparametric methodology1 it is not. On the other hand, because a carcinoma the size of a matchhead may, assuming a doubling time of 58 days, weigh 2 pounds 2 at the end of 2 years clinicians cannot quarrel with the conclusion that "If the patient has a potential survival of greater than 2 years an attempt should be made to control the local tumor". However, there is wide suspicion that local therapy is not enough. Early endocrine ablation is a certain method to prolong the lives of laboratory species with experimental adenocarcinoma of the prostate. 3 •4 Currently, a major private United States medical facility combines orchiectomy with radical prostatectomy. They have reported that "Orchiectomy significantly influenced progression in patients with Dl and prevented progression and PC death altogether in those with a DNA haploid tumor (42% of patients)". 5 Long-acting monthly depot injection of luteinizing hormone-releasing hormone agonists and antagonists will be approved shortly for interstate commercial promotion by more than 1 manufacturer. Under these circumstances, and considering the well known limitations of a retrospective nonrandomized series, must not a discussion of the justification for radiotherapy or surgical prostatectomy include a comparison with a matched group subjected to early (before macrometastases) luteinizing hormone-releasing hormone antagonism? Respectfully,

1. 2.

3. 4.

Anthony H. Horan 77 Wainwright Walla Walla, Washington 99362 Rickmers, A. and Todd, H. N.: Statistics: An Introduction. New York: McGraw-Hill Book Co., p. 394, 1967. Coffey, D.S. and Isaacs, J. T.: Experimental concepts in the design of new treatments for human prostatic cancer. In: Prostate Cancer. Geneva: International Union Against Cancer, p. 235, 1979. Grayhack, J. T.: Controversies in prostate cancer. Read at annual meeting of North Central Section, American Urological Association, Detroit, Michigan, September 16-19, 1987. Schally, A. V., Redding, T. W. and Comaru-Schally, A. M.: Inhibition of prostate tumors by agonistic and antagonistic analogs

of LH-RH. Prostate, 4: 545, 1983. 5. Zincke, H. and Utz, D. C.: Outcome of radical prostatectomy (RP) for patients with cancer of the prostate (PC) with extracapsular involvement including regional node metastasis. Read at annual meeting of North Central Section, American Urological Association, Orlando, Florida, November 13-19, 1988.

Reply by Authors. While it is obvious that patient mortality is secondary to metastatic prostate cancer, we disagree with the concept that residual locally active cancer poses no threat to the patient. The development of subsequent metastasis is increased in patients with documented residual cancer after definitive radiotherapy. 1 Local failures were included in the study analysis to reflect this increased progression risk. Any retrospective study is fraught with potential bias. To minimize any potential progression bias that treatment may introduce strict criteria were adopted. Residual cancer was not considered as failure unless the patient had documented symptoms related to local progression until the presence of symptomatic local disease prompted therapeutic intervention. Doctor Horan is correct in noting that we failed to include the percentage of local versus metastatic failures. Of 30 patients in the matched control group 20 demonstrated progression with 5 local failures compared to 4 with progression (1 locally) in the treatment group. In questioning the statistical significance of the study Doctor Horan has failed to appreciate the study design. The matched pairs analysis was used to evaluate any difference in treatment versus no treatment in this population. This provided a retrospective analysis in which the results would be expected to be highly significant. The unmatched pairs analysis was used to increase the data base and separate the results of each treatment group. Predictably, the results of this analysis were unable to differentiate clearly between the 2 treatment groups but there was a significant difference among both treatment groups and the no treatment group. Androgen ablation therapy has not been shown to be of benefit in the treatment of localized prostate cancer. Comparisons cannot be made between a series of patients with regionally advanced (stage Dl) disease as described by the Mayo Clinic reports and this study of patients with incidentally diagnosed cancer. 2 A brief analysis of the effect on probability of progression of androgen ablation therapy in this population was described in the companion paper. No beneficial effects could be identified in this population. 3 1. Scardino, P. T., Frankel, J. M., Wheeler, T. M., Meacham, R. B., Hoffman, G. S., Seale, C., Wilbanks, J. H., Easley, J. and Carlton, C. E., Jr.: The prognostic significance of post-irradiation biopsy results in patients with prostatic cancer. J. Urol., 135: 510, 1986. 2. Winkler, H. Z., Rainwater, L. M., Myers, R. P., Zincke, H., Farrow, G. M., Therneau, T. M., Nativ, 0., Raz, Y., Hosaka, Y., Boyle, E.T. and Lieber, M. M.: Prognostic significance of DNA ploidy in stage C and Dl prostate cancer. J. Urol., part 2, 139: 337A, abstract 698, 1988. 3. Lowe, B. A. and Listrom, M. B.: Incidental carcinoma of the prostate: an analysis of the predictors of progression. J. Urol., 140: 1340, 1988. RE: INTERMEDIATE-TERM SURVIVAL RESULTS IN CLINICALLY UNDERSTAGED PROSTATE CANCER PATIENTS FOLLOWING RADICAL PROSTATECTOMY W. J. Catalana, D.R. Miller and L. R. Kauoussi

J. Urol., 140: 540-543, 1988

To the Editor. The authors demonstrate that some patients whose disease was upstaged to C or Dl after radical prostatectomy survive without recurrence for extended periods without additional therapy. The actual 5-year survival for 9 stage C cancer patients was 67 per cent and for 12 with stage Dl disease it was 75 per cent. They suggest that this survival is comparable to our own stages C and Dl cancer patients who were treated with adjuvant radiation therapy, thus, suggesting that adjuvant radiation therapy has little effect on upstaged patients after radical prostatectomy. It is true that the survivals are similar: in a prior publication 1 and in our subsequent recent report2 the actuarial 5-year survivals free of disease were 80 per cent for 35 stage C cancer patients and 69 per cent for 36 stage Dl cancer patients, with 11 and 9 patients, respectively, at risk at 5 years. However, these numbers cannot be compared to this series for several reasons. Our stages C and Dl cancer patients were at higher risk for recurrent disease. Thus, we irradiated almost exclusively patients who had stage C disease by virtue of positive margins and/or positive seminal vesicles (97 per cent), whereas 6 of 9 with stage C

LETTERS TO THE EDITOR tumor had only capsular perforation-a group with decidedly better prognosis. Similarly, the lymph node metastases in the 12 stage Dl cancer patients were discovered on permanent section after frozen sections had been negative. We did not perform frozen sections in our patients but, rather, we performed radical prostatectomy on all patients without visible disease. Thus, we assembled a stage Dl cancer group with undoubtedly larger metastatic volume and, therefore, a worse prognosis. Also, and probably less importantly, bone scans were performed every 6 months in our series and only as needed by the authors-an arrangement that could significantly increase interval to recurrence in favor of the less scrutinized group. All of these points and counterpoints do not deter from the important message that radiation therapy is not a proved treatment and that controlled trials testing the effects of adjuvant radiation therapy or adjuvant endocrine therapy are needed urgently. Cooperative groups, such as ECOG and SWOG, are about to begin such studies. Because serum prostate specific antigen is an exquisitely sensitive marker for persistent and/or recurrent disease after radical prostatectomy these trials should be executed swiftly and accurately. Whenever possible, patients whose disease was upstaged after radical prostatectomy should be entered in these studies. Respectfully, Paul H. Lange Department of Urology, RL-10 University of Washington Seattle, Washington 98195 1. Lange, P.H., Moon, T. D., Narayan, P. and Medini, E.: Radiation

therapy as adjuvant treatment after radical prostatectomy: patient tolerance and preliminary results. J. Urol., 136: 45, 1986. 2. Lange, P. H., Reddy, P. K., Medini, E., Levitt, S. and Fraley, E. E.: Radiation therapy as adjuvant treatment after radical prostatectomy. Natl. Cancer Inst. Monogr., 7: 141, 1988.

Reply by Authors. Doctor Lange is correct in stating that our patients are not strictly comparable to the 45 patients reported on previously (reference 1 in Letter). However, we attempted to describe their patients as accurately as possible, stating that they were " ... stage C or Dl cancer patients with seminal vesicle invasion, positive anastomotic margins, marked capsular penetration associated with a Gleason grade of more than 7, or 6 or fewer microscopically positive nodes". We also included the caveat concerning the disease status of our own patients, stating that "It should be emphasized that these patients represent the earliest stages of extraprostatic cancer". We agree that the value of adjunctive radiation therapy in clinically understaged prostate cancer patients has not been demonstrated convincingly. The observation that persistently detectable prostate specific antigen titers after radical prostatectomy frequently fall into the undetectable range after adjunctive radiation therapy suggests a potential value of adjuvant radiation. However, long-term followup will be required before the curative potential can be established. In this regard patients treated with definitive radiation therapy may exhibit an early decrease in prostate specific antigen levels followed by a subsequent increase in patients whose tumors are not completely controlled.

RE: IS ANTIBIOTIC ADMINISTRATION INDICATED AFTER OUTPATIENT CYSTOSCOPY A. L. Manson

J. Urol., 140: 316-317, 1988 To the Editor. I read this article with great interest. I must confess that I found the method by which the author detected post-cystoscopy urinary infection to be inadequate and I thereby disagree with his conclusion. In the study the author took a single urine sample 2 weeks after cystoscopy for the urine culture. In my study of 1981 I took no less than 6 post-cystoscopy urine cultures on days 1, 2, 3, 6, 7 and 14.' I demonstrated that 91 per cent of all post-cystoscopy infections developed by 7 days after cystoscopy. All of these infections resolved spontaneously barring 1 and, thus, to take a single urine sample 14 days after cystoscopy will miss approximately 90 per cent of the postcystoscopy infections. In my study I demonstrated that no less than 16.6 per cent of the patients undergoing cystoscopy will have a postcystoscopy urinary infection. This is an astonishingly high figure, being roughly 5 to 6 times higher than all previously recorded data. The reason why my infection rate was so high was that I undertook 5 to 6 times the number of urine cultures as had been done in all previous

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studies and, indeed, as has been done in this study. This indicates, therefore, that a much more diligent search for post-cystoscopy bacteriuria is required than has been the usual practice. Clearly, the low incidence of post-cystoscopy bacteriuria in this study simply is a reflection of the fact that the author has not looked diligently enough for post-cystoscopy infections. Thus, no conclusion can be drawn to the efficacy of antibiotic prophylaxis, since my study shows that he is likely to have missed 90 per cent of these infections.

M. M. Hares Urology King & William Square 3 William Street South Chatham, Ontario N7M 6B3 Canada 1. Hares, M. M.: A double-blind trial of half-strength Polybactrin Soluble GU bladder irrigation in cystoscopy. Brit. J. Urol., 53: 62, 1981. Reply by Author. Doctor Hares uses his 1981 study to dispute my findings as well as those of other reports. After careful review of his study I have found that a direct comparison is difficult to make. My study specifically involves only those patients undergoing simple diagnostic cystoscopy in an outpatient setting, while Doctor Hares included all inpatients and many patients undergoing more prolonged therapeutic endoscopic procedures. In addition, his bacteriological results and clinical correlation are somewhat confusing. In his letter he states that urine cultures were obtained on days 1, 2, 3, 6, 7 and 14 from all patients when, in fact, the patients submitted dip slides that were collected at home and then forwarded to the investigators via the mail. In a review of his results there are clear discrepancies between the dip slide bacteriological findings and subsequent midstream urine cultures (when obtained). Some patients who had been treated by other physicians for presumed infections were included in the infection group despite sterile urine cultures. In designing my study my intent was to identify the incidence of clinically significant bacteriuria. Therefore, it was decided to include patients with either persistent asymptomatic bacteriuria (patients who may be at risk for later symptomatic infection) or symptomatic bacteriuria (infection). It was apparent that obtaining appropriately collected and processed urine cultures in asymptomatic outpatients on a frequent basis would prove to be impractical and time-consuming, and would guarantee inadequate patient compliance. By obtaining urine cultures in symptomatic patients at any time and at approximately 2 weeks in asymptomatic patients it was believed that all patients who are at risk for morbidity would be identified and allow for comparison when studying the possible advantages of antibiotic coverage. Transient asymptomatic bacteriuria that is present shortly after instrumentation and that rapidly resolves spontaneously is of questionable clinical significance and by definition is without morbidity. Therefore, earlier cultures were not obtained in asymptomatic patients. STONE COMPOSITION IS NO GUIDE TO STRENGTH: CHANGING THE DIRECTION OF RESEARCH?

To the Editor. For some time there has been research interest in trying to identify the composition of urinary stones before and during laser and shock wave fragmentation procedures. We question the usefulness of this interest and suggest an alternative direction for future research. Several reasons are given to pursue research into stone composition: 1) to predict the best wavelength of laser light to use for maximum effect, 2) to predict the degree of force (probably number and strength of shocks) needed to fragment a stone and 3) to determine the composition of small stone fragments that otherwise might be lost to observation. Reason 1 awaits confirmation that those few stones currently resistant to laser fragmentation are of predictable composition and can be broken with light of different wavelengths. Reason 3 is questionable in that, as currently understood, the process of laser interaction with stones involves light interaction only with surface layers and not with bulk composition;' this may restrict the usefulness of any derived information. The idea to predict stone strength from composition has been present for a long time. However, it has been well established that the chemical composition of stones is only 1 of many factors that determine their physical strength. Measured stone strengths and compositions are poorly correlated. 2 This can be understood from well established studies on other brittle materials, such as glass. The mechanical strength of a brittle material is affected greatly by its structure at the microscopic