- Email: [email protected]
Re: Discussion on Expectant Management of Prostate Cancer
1954
LETTERS TO THE EDITOR
12. Pilepich, M. V., Caplan, R., Al-Sarraf, M., John, M., Doggett, R. L. S., Sause, W. T., Lawton, C. A,, Abrams, R. A., Rotman, M., Rubin, P., Shipley, W. U. and Cox, J . D.: Phase I11 trial of hormonal cytoreduction in conjunction with definitive radiotherapy in locally advanced prostate carcinoma: the emerging role of PSA in the assessment of outcome. Int. J . Rad. Oncol. Biol. Phys., 27: 246, 1993. 13. Zelefsky, M., Leibel, S., Burmann, C., Kutcher, G., Mohan, R., Kelson, S. and Fuks, Z.: Early observations of acute and chronic toxicity and PSA response in patients with carcinoma of the prostate treated on a dose escalation study with 3DCRT. Int. J. Rad. Oncol. Biol. Phys., 3 0 156, 1994.
Reply by Authors. We are glad to see that our observations of more than 1 year ago that radiation therapy accelerates prostate cancer in approximately 80%of the patients are still of great concern to radiation oncologists. McKenzie notes that our original observations on the doubling time of PSA in untreated prostate cancer patients (reference 2 in Letter) are not "entirely comparable" to the radiation series we reported. However, the clinical stage B cancer patients are comparable and they represent the important stage. Clinical stage C cancer patients are mostly incurable and clinical stage A is so variable in residual cancer a t the time of definitive treatment that all therapeutic comparisons are largely meaningless. Moreover, all radiation oncologists continue to ignore the data of Bagshaw et a1 that patients with clinical stage B2 (T2b) cancer (unilobar palpable disease that extends for greater than half the distance of 1 lobe) had a 15-year survival rate of only 23%.' In addition, nothing was known about the metastatic status of the 23% of the patients who were alive. The data of Hancock et a1 (reference 6 in Letter) indicate a higher level of PSA as a definition of nonrelapsing status than we found, and the mean followupreported by Hanks et a1 (reference 7 in Letter) of 5 years is shorter than that in our patients. Consecutive PSA determinations 5 to 10 years after radiotherapy are critical. We would like to share information on a patient we recently saw in consultation who waited 1 year after diagnosis before starting 7,000 rad external beam radiotherapy (see figure). We believe he is representative of our patients. He was 70 years old in 1991 when he underwent 3 serial PSA determinations by the Hybritech assay before the start of radiotherapy. The normal magnetic resonance imaging showed a 39 gm. prostate. The prostate had a small questionable palpable abnormality, which was Gleason grade 4 + 3 on biopsy. The PSA decreased from 10.2 to 3.5 ng./ml. during the first 15 months after irradiation, which is a typical response. However, after the nadir PSA of 3.5 ng./ml. (a normal value), subsequent PSA levels showed a rapid doubling time of 5.6 months in comparison to the preradiation doubling time of more than 10 years. Observe that radiotherapy, while failing to cure the cancer, had decreased the size of the prostate by 36%despite greatly accelerating the growth rate of the cancer. Incidentally, the prostate was palpably normal on digital rectal examination when he was examined in late 1994, an observation that also confounded us in the pre-PSA irradiation years. While we cannot help the frustration that neither we nor anyone else obtained many pretreatment PSA values in the years during which our patients underwent irradiation (April 1985 to January 1988), there is no reason to question our observation that the mean doubling time of 37 clinical stage B prostate cancer patients in whom radiotherapy failed after reaching the nadir PSA level was 15
I
c z
m
>
I
6/91
1/92
6/92
12/92
6/93
9/93 12/93 6/94
9/94 10/94
DATE
PSA doubling time before and after radiation
months. Based on our 12 untreated stage B cancers (reference 2 in Letter) with a minimal followup of a t least 1year, 2 had stable serum PSA levels (an infinite PSA doubling time), 5 were doubling at intervals of more than 4 years and 5 were doubling the PSA level at 2 to 4-year intervals. In the closing paragraphs, McKenzie argues that even if radiotherapy fails to cure the patient, it may improve local control of the cancer in the pelvis. While this observation has been disputed in long-term followup (10 years) of prostate cancer patients after radiotherapy for clinical stage C disease,' it has nothing to do with our basic observation that irradiation accelerates the growth of prostate cancer in 80% of the patients. We also do not understand his concluding paragraph as to how randomization of stage C (T3) cancer patients to total androgen blockade with and without external beam radiation therapy will address our hypothesis (we prefer the word "observation") that radiation therapy alone accelerates the rate of cancer progression in 80% of the patients. Indeed, with the current unacceptable results of radiation therapy alone for prostate cancer, one can understand and applaud the recent trend of radiation oncologists everywhere to combine irradiation with additional cytotoxic hormonal therapy. All of us hope the results will be better but it will take 10 years to know whether combination therapy will exceed the current 20% cure rates. 1. Bagshaw, M. A,, Cox, R. S. and Ray, G. R.: Status of radiation treatment of prostate cancer a t Stanford University. Natl. Cancer Inst. Monogr., 7: 47, 1988. 2. Holzman, M., Carlton, C. E., Jr. and Scardino, P. T.: The frequency and morbidity of local tumor recurrence after definitive radiotherapy for stage C prostate cancer. J. Urol., 146: 1578, 1991.
RE: DISCUSSION ON EXPECTANT MANAGEMENT OF PROSTATE CANCER J . Urol., part 2, 1 5 2 1769-1772, 1994
To the Editor. In this discussion Dr. Gary J. Miller said that in 1929 Dr. Stanley Reiman concluded that "ultimately if the surgeon leaves cancer in the patient then the patient is going to die, and if the surgeon takes the cancer out then the patient will live." Since 1929, surgeons have changed their perception of residual tumor cells. In the National Surgical Adjuvant Breast and Bowel Project lumpectomy study patients treated by lumpectomy alone had a local recurrence rate of approximately 40%.' Radiation therapy decreased the local recurrence rate to less than 10%. Surprisingly, this 4-fold decrease in local recurrence rate did not improve overall survival. Several additional studies have supported this Apparently, a few cancer cells remain postoperatively but they seldom become a risk to patient survival. I have suggested a biological explanation for this surprising concl~sion.~ Fisher et a1 concluded correctly that local recurrence is a "marker for risk of, not a cause of, distant metastasis."6 They stated, "The discovery of IBTR (ipsilateral breast tumor recurrence) indicates that the patient was already at a greater risk of distant disease when the primary tumour was removed than the woman who has remained free of IBTR." Beginning in the 1920s several investigators in North America and Europe abandoned radical mastectomy. They completely removed the tumor using either partial to total (simple) None of these physicians ever returned to radical surgery. This was accomplished without the benefit of randomized trials. General surgeons are currently excising locally recurrent breast cancer following breast-sparing surgery. They understand that promptly treated recurrent disease is not a threat to survival. Perhaps urologists could benefit from these lessons already learned about breast cancer. There are no data to suggest that this perception of tumor-host balance does not apply to carcinoma of the prostate. Can localized prostate cancer be treated with limited surgery? Respectfully, Richard A. Evans 1101 Augusta Drive, Suite 210 Houston, Texas 77056-2015 1. Fisher, B., Redmond, C., Poisson, R.. Margolese, R., Wolmark, N., Wickerham, L., Fisher, E.. Deutsch, M., Caplan, R. and Pilch. Y.: Eight-year results of a randomized clinical trial
1955
LETTERS TO THE EDITOR comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. New Engl. J. Med., 320: 822, 1989. 2. Clark, R. M., Wilkinson, R. H., Miceli, P. N. and MacDonald, W. D.: Breast cancer. Experiences with conservation therapy. h e r . J . Clin. Oncol., 1 0 461, 1987. 3. Stehlin, J. S., Jr., de Ipolyi, P. D., Greef, P. J., Gutierrez, A. E., Hardy, R. J . and Dahiya, S. L.: A ten year study of partial mastectomy for carcinoma of the breast. Surg., Gynec. & Obst., 165: 191, 1987. 4. Stotter, A., Atkinson, E. N., Fairston, A., McNeese, M., Oswald, M. J. and Balch, C. M.: Survival following locoregional recurrence after breast conservation therapy for cancer. Ann. Surg., 212: 166, 1990. 5. Evans, R. A,: Preservation surgery for malignant disease: why it works. South. Med. J., 8 2 1534, 1989. 6. Fisher, B., Anderson, S., Fisher, E. R., Redmond, C., Wickerham, D. L., Wolmark, N., Mamounas, E. P., Deutsch, M. and Margolese, R.: Significance of ipsilateral breast tumor recurrence after lumpectomy. Lancet, 338 327, 1991. 7. Mustakallio, S. A,: Conservative treatment of breast carcinoma-review of 25 years follow up. Clin. Rad., 2 3 110, 1972. 8. Peters, M. V.: Radiation therapy in the management of breast cancer. In: Proceedings of the 6th National Cancer Conference. New York: J. B. Lippincott Co., pp. 163-174, 1970. 9. McWhirter, R.: Treatment of cancer of the breast by simple mastectomy and roentgenotherapy. Arch. Surg., 5 9 830,1949.
Reply by Doctor Miller. My remark was made regarding the need to intervene early in the natural history of high grade (grade 3) prostatic cancer. While Evans may be correct in stating that promptly treated recurrent disease is not a threat to survival for a subset of breast cancer patients, the picture is not as clear for those with prostatic cancer. Comparing radical mastectomy to nerve sparing prostatectomy ignores the fact that under the best of circumstances the margins of excision of a radical prostatectomy are relatively limited. I t is recognized that despite dramatic decreases in clinical stage at diagnosis, 40 to 50% of the patients who undergo radical prostatectomy have locally invasive disease.’ Patients with organ confined disease have only a 12%risk of failure at 10 years.’ However, the risk of failure increases to 30% for patients with capsule penetration and 60%with margin positive disease. Diseasefree survival even with adjuvant radiotherapy may be only 64%.3 Therapy for local recurrence is also not as easily accomplished within
the pelvis as it is in the breast. Presently, the efficacy of adjuvant radiotherapy is being studied in the National Cancer Institute, Intergroup Study INT 0086f.4 Until the results of such studies are known it seems premature to conclude that improved control of local recurrence in patients with prostate cancer will necessarily produce improved survival. It would seem, therefore, that early intervention in patients with moderate to high grade carcinoma of the prostate is a reasonable goal to pursue. 1. Partin, A. S. W., Borland, R. N., E stein, J. I. and Brendler, C. B.: Influence of wide excision of t i e neurovascular bundl44 on rognosis in men with clinically localized prostate cancer wit[ established capsular penetration. J. Urol., 1M): 142,1993. 2. Paulson, D. F., Moul, J. W. and Walther, P. J.: Radical prostatectomy for clinical stage T18NOMO prostatic adenocarcinoma: long-term results. J. Urol., 144: 1180, 1990. 3. Shevlin, B. E., Mittal, B. B., Brand, W. N. and Shetty, R. M.: The role of adjuvant irradiation following primary prostatectomy, based on histopathologic extent of tumor. Int. J. Rad. Oncol. Biol. Phys., 1 6 1425, 1989. 4. Thompson, I. M., Paradelo, J. C., Crawford, E. D., Coltman, C. A. and Blumenstein, B.: An opportunity to determine o timal treatment of pT3 prostate cancer: the window may be crosing. Urology, 44:804, 1994.
ERRATA ENDOPYELOTOMY Volume 153, Number 3, pages 701-703: The word “endopyelotomy” should have been used for the words “endoscopic pyelotomy” throughout this article.
INTERSTITIAL CYSTITIS Volume 153, Number 3, pages 728-729: The word “glomerulations” should have been used for the word “glomeruli”throughout this article.
LETTERS TO THE EDITOR
12. Pilepich, M. V., Caplan, R., Al-Sarraf, M., John, M., Doggett, R. L. S., Sause, W. T., Lawton, C. A,, Abrams, R. A., Rotman, M., Rubin, P., Shipley, W. U. and Cox, J . D.: Phase I11 trial of hormonal cytoreduction in conjunction with definitive radiotherapy in locally advanced prostate carcinoma: the emerging role of PSA in the assessment of outcome. Int. J . Rad. Oncol. Biol. Phys., 27: 246, 1993. 13. Zelefsky, M., Leibel, S., Burmann, C., Kutcher, G., Mohan, R., Kelson, S. and Fuks, Z.: Early observations of acute and chronic toxicity and PSA response in patients with carcinoma of the prostate treated on a dose escalation study with 3DCRT. Int. J. Rad. Oncol. Biol. Phys., 3 0 156, 1994.
Reply by Authors. We are glad to see that our observations of more than 1 year ago that radiation therapy accelerates prostate cancer in approximately 80%of the patients are still of great concern to radiation oncologists. McKenzie notes that our original observations on the doubling time of PSA in untreated prostate cancer patients (reference 2 in Letter) are not "entirely comparable" to the radiation series we reported. However, the clinical stage B cancer patients are comparable and they represent the important stage. Clinical stage C cancer patients are mostly incurable and clinical stage A is so variable in residual cancer a t the time of definitive treatment that all therapeutic comparisons are largely meaningless. Moreover, all radiation oncologists continue to ignore the data of Bagshaw et a1 that patients with clinical stage B2 (T2b) cancer (unilobar palpable disease that extends for greater than half the distance of 1 lobe) had a 15-year survival rate of only 23%.' In addition, nothing was known about the metastatic status of the 23% of the patients who were alive. The data of Hancock et a1 (reference 6 in Letter) indicate a higher level of PSA as a definition of nonrelapsing status than we found, and the mean followupreported by Hanks et a1 (reference 7 in Letter) of 5 years is shorter than that in our patients. Consecutive PSA determinations 5 to 10 years after radiotherapy are critical. We would like to share information on a patient we recently saw in consultation who waited 1 year after diagnosis before starting 7,000 rad external beam radiotherapy (see figure). We believe he is representative of our patients. He was 70 years old in 1991 when he underwent 3 serial PSA determinations by the Hybritech assay before the start of radiotherapy. The normal magnetic resonance imaging showed a 39 gm. prostate. The prostate had a small questionable palpable abnormality, which was Gleason grade 4 + 3 on biopsy. The PSA decreased from 10.2 to 3.5 ng./ml. during the first 15 months after irradiation, which is a typical response. However, after the nadir PSA of 3.5 ng./ml. (a normal value), subsequent PSA levels showed a rapid doubling time of 5.6 months in comparison to the preradiation doubling time of more than 10 years. Observe that radiotherapy, while failing to cure the cancer, had decreased the size of the prostate by 36%despite greatly accelerating the growth rate of the cancer. Incidentally, the prostate was palpably normal on digital rectal examination when he was examined in late 1994, an observation that also confounded us in the pre-PSA irradiation years. While we cannot help the frustration that neither we nor anyone else obtained many pretreatment PSA values in the years during which our patients underwent irradiation (April 1985 to January 1988), there is no reason to question our observation that the mean doubling time of 37 clinical stage B prostate cancer patients in whom radiotherapy failed after reaching the nadir PSA level was 15
I
c z
m
>
I
6/91
1/92
6/92
12/92
6/93
9/93 12/93 6/94
9/94 10/94
DATE
PSA doubling time before and after radiation
months. Based on our 12 untreated stage B cancers (reference 2 in Letter) with a minimal followup of a t least 1year, 2 had stable serum PSA levels (an infinite PSA doubling time), 5 were doubling at intervals of more than 4 years and 5 were doubling the PSA level at 2 to 4-year intervals. In the closing paragraphs, McKenzie argues that even if radiotherapy fails to cure the patient, it may improve local control of the cancer in the pelvis. While this observation has been disputed in long-term followup (10 years) of prostate cancer patients after radiotherapy for clinical stage C disease,' it has nothing to do with our basic observation that irradiation accelerates the growth of prostate cancer in 80% of the patients. We also do not understand his concluding paragraph as to how randomization of stage C (T3) cancer patients to total androgen blockade with and without external beam radiation therapy will address our hypothesis (we prefer the word "observation") that radiation therapy alone accelerates the rate of cancer progression in 80% of the patients. Indeed, with the current unacceptable results of radiation therapy alone for prostate cancer, one can understand and applaud the recent trend of radiation oncologists everywhere to combine irradiation with additional cytotoxic hormonal therapy. All of us hope the results will be better but it will take 10 years to know whether combination therapy will exceed the current 20% cure rates. 1. Bagshaw, M. A,, Cox, R. S. and Ray, G. R.: Status of radiation treatment of prostate cancer a t Stanford University. Natl. Cancer Inst. Monogr., 7: 47, 1988. 2. Holzman, M., Carlton, C. E., Jr. and Scardino, P. T.: The frequency and morbidity of local tumor recurrence after definitive radiotherapy for stage C prostate cancer. J. Urol., 146: 1578, 1991.
RE: DISCUSSION ON EXPECTANT MANAGEMENT OF PROSTATE CANCER J . Urol., part 2, 1 5 2 1769-1772, 1994
To the Editor. In this discussion Dr. Gary J. Miller said that in 1929 Dr. Stanley Reiman concluded that "ultimately if the surgeon leaves cancer in the patient then the patient is going to die, and if the surgeon takes the cancer out then the patient will live." Since 1929, surgeons have changed their perception of residual tumor cells. In the National Surgical Adjuvant Breast and Bowel Project lumpectomy study patients treated by lumpectomy alone had a local recurrence rate of approximately 40%.' Radiation therapy decreased the local recurrence rate to less than 10%. Surprisingly, this 4-fold decrease in local recurrence rate did not improve overall survival. Several additional studies have supported this Apparently, a few cancer cells remain postoperatively but they seldom become a risk to patient survival. I have suggested a biological explanation for this surprising concl~sion.~ Fisher et a1 concluded correctly that local recurrence is a "marker for risk of, not a cause of, distant metastasis."6 They stated, "The discovery of IBTR (ipsilateral breast tumor recurrence) indicates that the patient was already at a greater risk of distant disease when the primary tumour was removed than the woman who has remained free of IBTR." Beginning in the 1920s several investigators in North America and Europe abandoned radical mastectomy. They completely removed the tumor using either partial to total (simple) None of these physicians ever returned to radical surgery. This was accomplished without the benefit of randomized trials. General surgeons are currently excising locally recurrent breast cancer following breast-sparing surgery. They understand that promptly treated recurrent disease is not a threat to survival. Perhaps urologists could benefit from these lessons already learned about breast cancer. There are no data to suggest that this perception of tumor-host balance does not apply to carcinoma of the prostate. Can localized prostate cancer be treated with limited surgery? Respectfully, Richard A. Evans 1101 Augusta Drive, Suite 210 Houston, Texas 77056-2015 1. Fisher, B., Redmond, C., Poisson, R.. Margolese, R., Wolmark, N., Wickerham, L., Fisher, E.. Deutsch, M., Caplan, R. and Pilch. Y.: Eight-year results of a randomized clinical trial
1955
LETTERS TO THE EDITOR comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. New Engl. J. Med., 320: 822, 1989. 2. Clark, R. M., Wilkinson, R. H., Miceli, P. N. and MacDonald, W. D.: Breast cancer. Experiences with conservation therapy. h e r . J . Clin. Oncol., 1 0 461, 1987. 3. Stehlin, J. S., Jr., de Ipolyi, P. D., Greef, P. J., Gutierrez, A. E., Hardy, R. J . and Dahiya, S. L.: A ten year study of partial mastectomy for carcinoma of the breast. Surg., Gynec. & Obst., 165: 191, 1987. 4. Stotter, A., Atkinson, E. N., Fairston, A., McNeese, M., Oswald, M. J. and Balch, C. M.: Survival following locoregional recurrence after breast conservation therapy for cancer. Ann. Surg., 212: 166, 1990. 5. Evans, R. A,: Preservation surgery for malignant disease: why it works. South. Med. J., 8 2 1534, 1989. 6. Fisher, B., Anderson, S., Fisher, E. R., Redmond, C., Wickerham, D. L., Wolmark, N., Mamounas, E. P., Deutsch, M. and Margolese, R.: Significance of ipsilateral breast tumor recurrence after lumpectomy. Lancet, 338 327, 1991. 7. Mustakallio, S. A,: Conservative treatment of breast carcinoma-review of 25 years follow up. Clin. Rad., 2 3 110, 1972. 8. Peters, M. V.: Radiation therapy in the management of breast cancer. In: Proceedings of the 6th National Cancer Conference. New York: J. B. Lippincott Co., pp. 163-174, 1970. 9. McWhirter, R.: Treatment of cancer of the breast by simple mastectomy and roentgenotherapy. Arch. Surg., 5 9 830,1949.
Reply by Doctor Miller. My remark was made regarding the need to intervene early in the natural history of high grade (grade 3) prostatic cancer. While Evans may be correct in stating that promptly treated recurrent disease is not a threat to survival for a subset of breast cancer patients, the picture is not as clear for those with prostatic cancer. Comparing radical mastectomy to nerve sparing prostatectomy ignores the fact that under the best of circumstances the margins of excision of a radical prostatectomy are relatively limited. I t is recognized that despite dramatic decreases in clinical stage at diagnosis, 40 to 50% of the patients who undergo radical prostatectomy have locally invasive disease.’ Patients with organ confined disease have only a 12%risk of failure at 10 years.’ However, the risk of failure increases to 30% for patients with capsule penetration and 60%with margin positive disease. Diseasefree survival even with adjuvant radiotherapy may be only 64%.3 Therapy for local recurrence is also not as easily accomplished within
the pelvis as it is in the breast. Presently, the efficacy of adjuvant radiotherapy is being studied in the National Cancer Institute, Intergroup Study INT 0086f.4 Until the results of such studies are known it seems premature to conclude that improved control of local recurrence in patients with prostate cancer will necessarily produce improved survival. It would seem, therefore, that early intervention in patients with moderate to high grade carcinoma of the prostate is a reasonable goal to pursue. 1. Partin, A. S. W., Borland, R. N., E stein, J. I. and Brendler, C. B.: Influence of wide excision of t i e neurovascular bundl44 on rognosis in men with clinically localized prostate cancer wit[ established capsular penetration. J. Urol., 1M): 142,1993. 2. Paulson, D. F., Moul, J. W. and Walther, P. J.: Radical prostatectomy for clinical stage T18NOMO prostatic adenocarcinoma: long-term results. J. Urol., 144: 1180, 1990. 3. Shevlin, B. E., Mittal, B. B., Brand, W. N. and Shetty, R. M.: The role of adjuvant irradiation following primary prostatectomy, based on histopathologic extent of tumor. Int. J. Rad. Oncol. Biol. Phys., 1 6 1425, 1989. 4. Thompson, I. M., Paradelo, J. C., Crawford, E. D., Coltman, C. A. and Blumenstein, B.: An opportunity to determine o timal treatment of pT3 prostate cancer: the window may be crosing. Urology, 44:804, 1994.
ERRATA ENDOPYELOTOMY Volume 153, Number 3, pages 701-703: The word “endopyelotomy” should have been used for the words “endoscopic pyelotomy” throughout this article.
INTERSTITIAL CYSTITIS Volume 153, Number 3, pages 728-729: The word “glomerulations” should have been used for the word “glomeruli”throughout this article.