Prostate Specific Antigen Values after Radical Retropubic Prostatectomy for Adenocarcinoma of the Prostate: Impact of Adjuvant Treatment (Hormonal and Radiation)

*

MYERS

AND

From the Department of Urology and the Division of Laboratory Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota

Prostate et al in 1979. of 33,000, and is cells normal prostate and prostate cancer. 2 PSA also is 3 and is ImmlJn~)lo,gH~alJlV Ph~)spJhatase. Its half-life has

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measllre:ments of that corTes,pOlndE~d 2 standard deviations. The reference ranges for men are agewas 0.1 delJerldent. The median value for 28 men 18 to 40 years old was 0.5 ng.jmI., for 29 men 41 to 50 years old it was 0.8 ng.jmI., for 18 men 51 to 60 years old it was 1.0 ng.jmI. and for 20 men 61 to 75 years old it was 1.9 ng.jmI. The 95% reference ranges for men with normal prostate glands were set at less than 2.8 ng.j ml. for men less than 40 years old and less than 4.0 ng.jmI. for men more than 40 years old. All of the women had values of less than 0.1 ng.jmI. Based on the data in women and the analytic reproducibility of the assay, the reference value for

PSA levels ::lv:::nl::lhlp. t"ath()10Il?;lC,al stage was SPE:~CUneln. Cancer to the ""~ ,...+'"'+.,,.. sule was as either pathological stage A \.. . . ,., ".. rectal prostatic examination before original diagnosis by transurethral resection) or pathological stage B. Cancer extension through the prostatic capsule into periprostatic fat was classiIJ'ULJLFl.A.'v'UL.A.

'l,A. ...

Accepted for publication July 24, 1990. * Current address: Section of Urology, Yale University, New Haven, Connecticut 06510. t Requests for reprints: Mayo Clinic, 200 First St. SW, Rochester, Minnesota 55905. :I: Hybritech, Inc., San Diego, California.

§ Iso-Data, Inc., Rolling Meadows, Illinois.

319

320

MORGAN AND ASSOCIATES

women and men without a prostate gland was set at 0.2 ng./ ml. or less. RESULTS

Of the 192 patients studied 78 (41 %) had pathological stage A or B, 35 (18%) had stage C, 48 (25%) had stage C+ and 31 (16%) had stage Dl cancer. PSA levels were first measured an average of 4.75 months postoperatively. In 95% of the patients the initial postoperative measurement was made 8 months or less after the operation and all initial levels were measured before 12 months. Of the patients with intracapsular disease (stage B2 or less) 82% had PSA levels of 0.2 ng./ml. or less postoperatively, while 86% of those with stage C and 65% of those with stage C+ disease had postoperative levels in the female range. In 90% of the patients with lymph node involvement (stage Dl) PSA levels decreased to 0.2 ng./ml. or less after treatment. Many higher stage cancer patients received adjuvant therapy, either endocrine or radiation. Virtually all patients with lymphatic metastasis were treated with immediate adjuvant orchiectomy and a large proportion of those with stage C or C+ disease received additional treatment beyond an operation (see table). For patients who received no adjuvant therapy 63 of 77 (82%) with pathological stage A or B, 18 of 21 (86%) with pathological stage C, 16 of 28 (57%) with pathological stage C+ and 1 of 2 with pathological stage D1 tumors had postoperative PSA levels of 0.2 ng./ml. or less. Of those who received hormonal therapy in any form (orchiectomy or oral hormones) 1 of 1 (100%) with pathological stage A or B, 5 of 6 (83%) with pathological stage C, 8 of 9 (89%) with pathological stage C+ and 27 of 29 (93%) with pathological stage Dl tumors had postoperative PSA levels of 0.2 ng./ml. or less. At most recent followup (mean 321 days) 26 of these 29 patients (90%) continue to have PSA values of 0.2 ng./ml. or less and no evidence of disease. Of those 19 patients who received radiotherapy alone 7 of 8 (88%) with pathological stage C and 7 of 11 (64%) with pathological stage C+ disease had postoperative PSA levels of 0.2 ng./ml. or less when first measured. Figure 1 compares all adjuvant treated patients with those treated by an operation alone for each pathological stage by using the initial PSA value postoperatively. For stages C and C+ disease adjuvant therapy did not significantly (p = 0.2 for stage C+) affect the first postoperative PSA measurement. However, therapy had not been completed at the time of this measurement in 44% of the patients treated with adjuvant radiation. Adjuvant radiotherapy as a single modality was delivered at the discretion of the treating surgeon to 19 patients, 13 of whom had positive surgical margins. Treatment began an average of 77.5 days postoperatively (range 28 to 180 days). Patients treated with adjuvant radiotherapy can be subdivided into 5 groups: 1) 3 patients whose PSA values initially were greater than 0.2 ng./ml. postoperatively and subsequently decreased to the female range with adjuvant radiation, 2) 2 patients as in group 1 except that the PSA level begins to increase after radiotherapy has been completed, 3) 13 patients with PSA values of 0.2 ng./ml. or less before adjuvant radiotherapy that remain low, 4) 1 patient with a PSA value of more than 0.2 ng./ml. postoperatively that remained elevated despite adjuvant

radiotherapy and 5) 1 patient whose PSA value initially was 0.2 ng./ml. or less but it subsequently increased and radiotherapy was instituted, and the PSA level subsequently decreased again to 0.2 ng./ml. or less. Positive surgical margins were noted in 2, 1,8, 1 and 1 patient, respectively. Figure 2 shows the PSA levels with time in 8 of 19 adjuvant radiated stage C or C+ cancer patients. Eleven patients in group 3 are not shown. To determine the effect of adjuvant radiation on PSA levels in stages C and C+ lesions values were plotted at 1 year ± 90 days postoperatively in the 50 stage C or C+ cancer patients with adequate followup (fig. 3). In 16 of 17 patients (94%) treated with adjuvant radiation PSA levels decreased to less than 0.2 ng./ml., whereas only 21 of 33 (64%) without adjuvant treatment had a similar decrease in PSA levels (p = 0.02). Among 83 patients with pathological stage C or C+ disease 21 of 29 (72%) with positive surgical margins (residual cancer) had postoperative PSA levels in the female range. This finding was not significantly different from those without positive margins-40 of 54 (74%) had a PSA level of 0.2 ng./ml. or less. However, the group with positive margins had a higher frequency of adjuvant therapy: 23 of 29 (79%) without adjuvant treatment versus 11 of 54 (20%) in the negative margin group (p <0.001). For all patients with positive margins more of those with adjuvant treatment had female PSA values (78%) than those without adjuvant treatment (50%). However, this difference was not significant (p = 0.17). Nuclear deoxyribonucle7:c acid (DNA) ploidy and PSA level. A total of 63 patients had DNA flow cytometry data available for review. Of 45 patients with DNA diploid tumors 36 (80%) had a PSA level in the female range (0.2 ng./ml. or less) postoperatively, compared to 12 of 18 (67%) with DNA nondiploid tumors (16 tetraploid and 2 aneuploid). These 2 groups were not different from each other (p >0.26). DISCUSSION

Initial excitement over the potential use of PSA as a tumor marker has been dampened somewhat by the realization that PSA is not specific to prostate cancer and is normally found in the serum of healthy men. With 4 ng./ml. as the upper limit of normal for the Tandem-R assay, Ercole et al reported that 21 % of 357 patients with benign prostatic hyperplasia had increased levels, with 7% twice normal and 3% with levels greater than 10 ng./ml., whereas only 2 of 30 (7%) with pathologically proved intracapsular prostate cancer had PSA levels of more than 10 ng./m1. 6 Others also have found that the patients with benign prostatic hyperplasia have PSA levels that are statistically indistinguishable from those with intracapsular prostate cancer. 4 Serum PSA values also can be increased by prostatic massage, cystoscopy and biopsy.7 Therefore, because of the overlap in PSA levels between malignant and benign prostatic conditions PSA is not an accurate screening tool for prostate cancer. 7,8 It was hoped that PSA might serve as an accurate preoperative predictor of pathological stage and, therefore, aid in the selection of patients who would benefit from definitive local therapy. 6 Indeed, PSA levels have been found to correlate well with tumor volume and clinical stage in patients with prostate

Type of adjuvant treatment by pathological stage Pathological Stage

Total No. Pts.

A+B

78 35 48 31

C

C+ Dl

* Hormones given orally. t Radiation plus hormones given orally.

No Adjuvant Treatment No. Pts. (%) 77 21 28 2

(99) (60) (58) (6)

Orchiectomy No. Pts.

(07)

Radiation No. Pts.

Hormones* No. Pts.

/0

(%)

(%)

4 (11) 7 (15) 28 (90)

8 (23) 11 (23)

Combinationt No. Pts. (%)

1 (1) 2 (6)

0

2 (4) 1 (3)

Total Adjuvant Treatment No. Pts. 1 14 20 29

(1) (40) (42) (94)

tissue. Of 78 men in our series pathologically ,....,.1-· ... '-~U\l cancer (stage B2 or less) who underwent ~ ... 1-'n."VV'\,~7 values decreased to female levels in 64 Of 51 patients with pathologically intracapsular lesions treated by Hortin et al only 36 (71 %) had PSA values of 0.2 ng.jml. or less postoperatively9 but the Hopkins group reported that 76 of 81 patients (94%) with cancer confined pathologically to the prostate had PSA levels of 0.2 ng./ml. or less after radical retropubic prostatectomy.4 It can be assumed that an increased PSA level after radical retropubic prostatectomy is indicative of residual (local and/or systemic) or recurrent disease.4,8,9 If disease truly is confined histologically within the prostate it is puzzling how residual cancer could be present after a properly performed radical prostatectomy. Several possible explanations can be proposed. Local extraprostatic disease may not be detected during pathological examination because lesions are often multifocal and all surgical margins may not be examined routinely. Occult lymphatic metastasis may not be detected by lymphadenectomy or the existence of skeletal metastasis undetectable radionuclide bone may rise to an increased after radical prostatectomy in a few seeding the bed may occur if the is of the needle tract after tranS1Jerlviolated. neal has been reported in as many as 1 % of the cases. 10 Benign prostatic tissue left behind after radical prostatectomy is an additional consideration. An 18% incidence of increased PSA levels after radical retropubic prostatectomy for pathologically sular disease is conspicuous when considering the excellent clinical results achieved in this identical to that of an age-matched surgical the effects of small volume residual disease may not be when COlI1S1de:nn.g crude or survival in an older in whom outcome often is more on other ""'~n1-'....,.N' causes of death. results of 1-h"".n"""~7 may assessed more disease gression rather than survival. the -ror\A-r-tori year rate from this institution for 'Y\+· ... or.CI,,'o ... lesions of 83%11 matches percentage of r.ACl1-A~l"\"'01I-'~Tl"\ PSA 0.2 """.", ..... 1-,,,1-'"

o ,... "....,

1J ...

Stage A + B n = 77

Stage C + n = 28 n = 20

Stage C n = 21 n = 14

Stage D-1 n = 29

FIG. 1. PSA after radical retropubic prostatectomy with or without adjuvant treatment (Rx).

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Female level

0.10 Preoperative PSA

50

100

150

200

250

300

350

400

450

500

550

Time, days postoperatively

2. Adjuvant radiation after radical retropubic prostatectomy. Each line represents individual stage C or C+ cancer patient treated with adjuvant radiation. Not shown are 11 patients with immediate decrease of PSA to 0.1 ng./ml. or less postoperatively. FIG.

No adjuvanlt Rx Adjuvant radiation

I

*

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1-yr ± 90-day postop n =33 n= 17

=0.02

3. PSA after radical retropubic prostatectomy in stages C and C+: effect of adjuvant radiation. FIG.

cancer. 8 However, capsular perforation can occur at low tumor volumes 7 and, therefore, it cannot be predicted by PSA alone. Thus, PSA levels cannot reliably discriminate between pathological stages Band C. However, it has been suggested that small amounts of capsular perforation may not be prognostically significant. 8 Oesterling et al demonstrated that on an individual basis PSA levels cannot accurately predict the true extent of prostate cancer: false positive rates ranged between 62 and 86% despite adjustments in the upper limit of norma1. 4

those ((leIJlnea as tumor into 19% for those with seminal vesicle or hTY1r'\nt"\arl1"' ln~H'I"UiP·mt=lnt" 4 whereas 43% of the na-thr\IAI"l',I"',al lesions in another series were with po~stopeJratlve PSA levels in the female range. 9 These results suggest that an operation alone may be less than satisfactory for higher stage lesions. Indeed, of 280 patients with pathological stage C lesions treated at our clinic with radical retropubic prostatectomy alone (mean followup 4.5 years) 25% had progression. 12 External beam radiation therapy has been used successfully in the adjuvant setting after radical prostatectomy for extracapsular disease in the prevention of local recurrence. 12 ,13 In our series there were significantly more patients in the adjuvant irradiated group with PSA values in the female range compared with those without adjuvant therapy (p = 0.02). This difference pe:ne1~ratlo'n

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322

MORGAN AND ASSOCIATES

was seen at 1 year of followup. Of concern, however, is the finding that in the 2 patients with the longest followup PSA levels began to increase again after reaching female levels 1 year postoperatively (fig. 3). Long-term followup will be required to answer this question. In the past, patients have been selected for adjuvant therapy based on the pathological findings at radical retropubic prostatectomy. However, PSA as a marker of viable prostatic tissue should be an accurate indicator of the presence of residual or recurrent disease and, therefore, may be a useful discriminator in selecting patients for adjuvant therapy. In this way adjuvant treatment (with its added morbidity) can be withheld until disease is documented biochemically by increasing PSA values. The response to therapy can then be monitored with sequential PSA values. In 1 study 26 of 56 patients with an increased PSA level after radical retropubic prostatectomy had positive random needle biopsies of the urethrovesical anastomosis. Of the 26 patients 19 were treated with adjuvant radiation therapy and PSA decreased to female levels in 50%.14 A beneficial effect of adjuvant endocrine therapy in prostate cancer with positive nodes is suggested by the favorable decrease in PSA levels after radical retropubic prostatectomy combined with adjuvant orchiectomy seen in our series (96% had levels of 0.2 ng./ml. or less). This did not change significantly in the short followup available (mean 321 days)-90% of the PSA values were still 0.2 ng./ml. or less. However, other factors may be affecting the serum concentration of PSA that do not correlate with a therapeutic effect of treatment. There is experimental evidence to suggest that PSA expression may be affected by endocrine manipulation via a mechanism other than cellular death. Csapo et al measured PSA levels and tumor volumes before and after endocrine therapy in Balb/c nude mice implanted with human prostate cancer cell lines. 15 Although tumor volume and PSA level decreased after endocrine therapy, PSA level decreased disproportionately. The ratio of serum PSA level (ng./ml.)-to-tumor volume (mm. 3 ) decreased as much as 19-fold. Therefore, after endocrine therapy serum PSA levels were lower due to an effect other than tumor volume. Bruchovsky et al suggested that androgen withdrawal in prostate cancer results in death of the majority of cells (the hormonally sensitive population) while a group of stem cells, resistant to the altered hormonal milieu, continues to survive. 16 These androgen-independent stem cells are the more primitive, undifferentiated cells that serve a progenitor function and eventually proliferate in the face of androgen deprivation, giving rise to a relapse after endocrine therapy.16,17 Because these androgen-independent cells are undifferentiated, we might postulate that they also are not capable of performing the functions of a mature prostatic epithelial cell and, therefore, cannot synthesize PSA. 16 This concept is supported by Partin et aI, who measured PSA and tumor volume in 350 men with localized prostate cancer treated with radical prostatectomy.18 There was a negative correlation between serum PSA level and Gleason score when adjustments were made for tumor volume (tumor volume must be taken into consideration, since higher grade lesions usually also are larger).18 Likewise, previous studies and our own experience have demonstrated poor PSA staining in undifferentiated specimens of prostate cancer. 19 Keillor and Aterman reported that 12 of 20 poorly differentiated prostate cancers showed no staining by PSA. 19 PSA staining has been shown to be minimal in the normal, viable prostate gland of boys 6 months to 10 years old when serum testosterone levels are at their lowest. 2o As these reports suggest, one would not necessarily expect the growth of hormonally resistant prostate cancer cells to be associated with an increase in PSA level. Therefore, a low PSA level after any treatment that includes hormonal therapy may not adequately reflect the presence of residual or recurrent disease.

The effect of residual disease on postoperative PSA levels could not be determined in our study because of the disproportionate use of adjuvant therapy in this group. However, patients with positive margins who received adjuvant therapy tended to have lower PSA values than those who did not receive it (p = 0.17). This seems to correlate with a previous finding of a statistically significant positive effect of adjuvant treatment in preventing local recurrence in 93 lesions with positive margins evaluated retrospectively.21 REFERENCES 1. Wang, M. C., Valenzuela, L. A., Murphy, G. P. and Chu, T. M.: Purification of a human prostate specific antigen. Invest. Urol., 17: 159, 1979. 2. Nadji, M., Tabei, S. Z., Castro, A., Chu, T. M., Murphy, G. P., Wang, M. C. and Morales, A. R.: Prostatic-specific antigen: an immunohistologic marker for prostatic neoplasms. Cancer, 48: 1229,J981. 3. Wang, M. C., Papsidero, L. D., Kuriyama, M., Valenzuela, L. A., Murphy, G. P. and Chu, T. M.: Prostate antigen: a new potential marker for prostatic cancer. Prostate, 2: 89, 1981. 4. Oesterling, J. E., Chan, D. W., Epstein, J. I., Kimball, A. W., Jr., Bruzek, D. J., Rock, R. C., Brendler, C. B. and Walsh, P. C.: Prostate specific antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostatectomy. J. Urol., 139: 766, 1988. 5. Zincke, H., Fleming, T. R., Furlow, W. L., Myers, R. P. and Utz, D. C.: Radical retropubic prostatectomy and pelvic lymphadenectomy for high-stage cancer of the prostate. Cancer, 47: 1901, 1981. 6. Ercole, C. J., Lange, P. H., Mathisen, M., Chiou, R. K., Reddy, P. K. and Vessella, R. L.: Prostatic specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with prostatic cancer. J. Urol., 138: 1181, 1987. 7. Stamey, T. A., Yang, N., Hay, A. R., McNeal, J. E., Freiha, F. S. and Redwine, E.: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. New Engl. J. Med., 317: 909,1987. 8. Stamey, T. A., Kabalin, J. N., McNeal, J. E., Johnstone, I. M., Freiha, F., Redwine, E. A. and Yang, N.: Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. II. Radical prostatectomy treated patients. J. Urol., 141: 1076,1989. 9. Hortin, G. L., Bahnson, R. R., Daft, M., Chan, K.-M., Catalona, W. J. and Ladenson, J. H.: Differences in values obtained with 2 assays of prostate specific antigen. J. Urol., 139: 762, 1988. 10. Moul, J. W., Miles, B. J., Skoog, S. J. and McLeod, D. G.: Risk factors for perineal seeding of prostate cancer after needle biopsy. J. Urol., 142: 86, 1989. 11. Benson, R. C., Jr., Tomera, K. M., Zincke, H., Fleming, T. R. and Utz, D. C.: Bilateral pelvic lymphadenectomy and radical retropubic prostatectomy for adenocarcinoma confined to the prostate. J. Urol., 131: 1103,1984. 12. Zincke, H.: Bilateral pelvic lymphadenectomy and radical retropubic prostatectomy for stage C or D1 adenocarcinoma of the prostate: possible beneficial effect of adjuvant treatment. NatI. Cancer Inst. Monogr., 7: 109, 1988. 13. 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. 14. Lightner, D. J., Reddy, P. K. and Lange, P. H.: PSA response to radiation therapy (RT) after radical prostatectomy (RP): correlation with biopsy (BX) and rectal exam. J. Urol., part 2, ·141: 183A, abstract 55, 1989. 15. Csapo, Z., Brand, K., Walther, R. and Fokas, K.: Comparative experimental study of the serum prostate specific antigen and prostatic acid phosphatase in serially transplantable human prostatic carcinoma lines in nude mice. J. Urol., 140: 1032, 1988. 16. Bruchovsky, N., Brown, E. M., Coppin, C. M., Goldenberg, S. L., Le Riche, J. C., Murray, N. C. and Rennie, P. S.: The endocrinology and treatment of prostate tumor progression. Prog. Clin. BioI. Res., 239: 347, 1987. 17. Isaacs, J. T.: The timing of androgen ablation therapy and/or chemotherapy in the treatment of prostatic cancer. Prostate, 5: 1,1984.

of localized prostate cancer: influvolume and benign hyper-

dit:le]~enlti~ltic)n; tumor

differen-

and prostate specific antigen. J. Urol., 21. Morgan, Zincke, and Bergstralh, Residual cancer (RC) after bilateral pelvic lymphadenectomy (PLA) and radical retropubic prostatectomy (RP) for stage C prostate cancer (PC): impact on local and systemic progression and cause specific 505A, abstract 1361, 1989. survival. J. Urol., part 2,