Reference range for prostate-specific antigen levels after external beam radiation therapy for adenocarcinoma of the prostate

ADULT

UROLOGY

REFERENCE RANGE FOR PROSTATE-SPECIFIC ANTIGEN LEVELS AFTER EXTERNAL BEAM RADIATION THERAPY FOR ADENOCARCINOMA OF THE PROSTATE ROBERT W. GEIST. M.D. From the Metropolitan

Urologic

Specialists, PA., St. Paul, Minnesota

ABSTRACT-Objectives. To determine a reference range for prostate-specific antigen (PSA) in patients who have had external beam radiation therapy for adenocarcinoma of the prostate. Methods. Serum PSA levels were serially measured with the Hybritech Tandem-R assay in 35 patients who had completed radiation therapy for a mean of 5 1 f 32 months (range, 10 to 133). Results. Serum PSA levels that were greater than 2.0 ng/mL (n = 20) continued to rise at a rate of more than 1 ng/mL per year, whereas levels between 0.0 and 2.0 ng/mL (n = 15) remained stable for an average of 7 1 f 32 months (range, 22 to 133). One of these latter 15 patients had a false-negative PSA level when he experienced a biopsypositive prostate nodule and positive bone scan 43 months after therapy. Conclusions. Prostate cancer control after radiation therapy was indicated in most men by a PSA reference range of 0.0 to 2.0 ng/mL. Cancer activity was indicated in all men with levels above this range.

When prostate-specific antigen (PSA) measurement became clinically available in 1988, there was no published information about what happened to levels of the marker after radiation therapy for cancer of the prostate. Therefore, we began serial measurements of PSA on a group of 35 patients who had completed radiation therapy and continued these measurements until 6 years after the last man had finished treatment. During these 6 years, other authors were finding that rising PSA levels presaged clinical relapse after all forms of treatment, including radiationleg and several authors proposed that use of serial PSA measurements could reveal treatment failure earlier than traditional signs of local or systemic cancer recurrence.4J,9-11 Such a practice presupposes knowledge of a normal (reference) range. Because some viable noncancerous prostate tissue may remain in situ after radiation, the reference range can be expected to differ from that in patients who have undergone radical prostatectomy. Although attempts Submitted July 28, 1994, accepted (with revisions): December 9,1994

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are being made to delineate a postradiation PSA reference range, there is none at this time with which to gauge treatment success or failure.1°J2 Two questions need answering before PSA levels can be profitably used in fixing the time of failure after radiation therapy: what rate of PSA rise represents significant cancer activityl’ and when, if ever, do PSA levels reliably indicate cancer contro1?3,4,6J3 Our serial PSA measurements provide tentative answers to these questions and may help to delineate a standard reference range after radiation therapy MATERIAL

AND METHODS

P~PULL~TION

The 35 patients had completed radiation therapy months or years before the study was begun. They had been treated at a single institution by external beam radiation using a 10 MeV linear accelerator. The mean total dose of radiation given to the prostate and pelvis was 6520 * 118 cGy (range, 6000 to 6800 cGy). Their average age was 70.5 * 5.9 years (range, 52 to 82). The disease had been staged after needle biopsy of the prostate in 25 men and after transurethral resection in 7. The disease UROLOGY@ /JUNE 1995 I VOLUME 45, NUMBER 6

40 35 30 24 22

lb

i0

3b

40

Months

i0

60

after Radiation

i0

I 80

I 90

100 I

-I1 0

Therapy

Serum prostate-specific antigen (PSA) values over time in 20 men with rising concentrations. Shaded area (less than 2 ng/mL) is reference range determined in this study; dotted line marks standard upper limit of normal for assay. FIGURE 1.

had been staged in the remaining 3 after radical prostatectomy They were included because, like the patients with a prostate nodule, they appeared to have localized cancer in the pelvis; 2 of these 3 had a positive needle biopsy of a pelvic nodule at 4 and 6 years after radical perineal prostatectomy, and 1 had a positive pathologic margin after a radical retropubic prostatectomy The disease was Stage B in 26 men and Stage C in 9. The average Gleason score was 5.1 * 1.2. Of these 35 men, 29 had undergone radiation because of medical contraindications to radical prostatectomy 3 had chosen radiation as an alternative to surgery, and, as already noted, 3 had already had surgery at the time radiation was given. Before radiation, all men had normal serum prostatic acid phosphatase levels and negative bone scans. None of the men had received any hormone therapy before the study was initiated. No PSA measurements had been done before or during radiation treatment.

phosphatase measurements were discontinued when, with only one exception, the values did not rise concomitant with rising PSA levels. Routine bone scans were likewise discontinued when none was positive at the time of rising PSA levels. The initial PSA measurements were done at a mean of 32 + 20 months (range, 8 to 76) after completion of radiation therapy The final PSA measurements were done at a mean of 51 + 32 months (range, 10 to 133). Patients were closed from the study when rising PSA levels (20 cases) or a new biopsy-positive palpable prostate mass (1 case) gave evidence of cancer progression. However, plotting of PSA values was continued until hormone treatment was started. Patients with no evidence of cancer recurrence were closed from the study when they either died of other causes (7 cases), or were lost to follow-up (3 cases>, or at 72 months after the last man had completed therapy (4 cases>. STATISTICS

METHODS

Follow-up examinations were done initially using digital rectal examination (DRE), measurement of serum acid phosphatase, and bone scans. The PSA levels were determined using the Tandem-R assay (Hybritech, San Diego, Calif) with the lower limit of sensitivity being 0.1 ng/mL. Acid UROLOGY@ /JUNE

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The difference between means was analyzed using a two-tailed t test. RESULTS After serial PSA measurements had been plotted, two groups of patients became evident: those with rising PSA levels and those with stable levels (Figs. 1 1017

3 2 1 0 0

10

20

30

40

50

Months

60

70

80

after Radiation

90

100

110

120

130

1

Therapy

Serum prostate-specific antigen [PSA) values over time in 15 men with stable concentrations. One patient proved to have falsely negative findings. FIGURE 2.

TABLE I.

Patient

population

Pretreatment

Age

(MT;;~;~SD) PSA Rising (n=20) Stable (rl = 15) KEY:

70.5 * 5.0 (52-77) 70.6 + 6.9 (60-82)

PSA= prostate-spec$c

Status

Sti;gy B Stage C Gleason Sum n (n) (Mean + SD) 15

5

5.3 + 1.1

11

4

4.8 f 1.2

antigen

and 2). There was no statistical difference between the two groups’ mean age (P = 0.814), stage (P = 1 .O>, or Gleason sum (P = 0.453) (Table I). Of the 35 men, 20 (57%) showed PSA levels rising at a rate of more than 1 ng/mL per year at an average of 35 + 21 months (range, 10 to 80) after completing radiation therapy. When PSA never fell below 2 ng/mL or when it rose above 2 ng/mL, it invariably continued to rise at a rate of more than 1 ng/mL per year (Fig. 1). This suggested significant cancer activity. One man had a single initial PSA measurement of 13.0 ng/mL and a prostate nodule; he was treated with salvage prostatectomy, after which his PSA dropped to 0.1 ng/mL but later rose again. When the serum PSA was more than 2 ng/mL and rising at more than 1 ng/mL per year, the patient was closed from the study. At that time, the median PSA value was 4.35 ng/mL, and the average was 6.0 f 4.9 ng/mL (range, 2.3 to 23.3 ng/mL). Three men had PSA levels more than 10 ng/mL. Nine men had prostate nodules compared with 6 when PSA was initially measured. One patient with

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a pelvic nodule found after radical perineal prostatectomy no longer had a nodule after radiation therapy but, when closed from the study, his PSA level had risen to 3.4 ng/mL at 34 months. Ten men had bone scans, all of which were negative, including those in 2 men whose PSA levels were 10.1 and 13.0 ng/mL. One man with a PSA value of 23.3 ng/mL refused a scan. Fifteen of the men had stable PSA levels when followed for an average of 71 * 32 months (range, 22 to 133) after completing radiation therapy (Fig. 2). Two died of unrelated causes and 1 was lost to follow-up by 34 months. The remaining 12 were followed from 43 to 133 months after therapy had been finished. One developed a biopsy-positive prostate nodule and a positive bone scan at 43 months and was treated with hormones. On hormone therapy, his nodule disappeared, and his PSA dropped to 0.4 ng/mL but eventually rose to more than 2 ng/mL. None of the other 11 men (including 2 w h o h ad undergone radical prostatectomy) had clinical or chemical evidence of relapse at a mean of 84 months (range, 44 to 133; median, 96). When the 15 men with stable PSA levels were closed from the study, their median PSA value was 0.7 ng/mL, and their average PSA level was 0.9 ng/mL f 0.7 ng/mL (range, 0.1 to 1.9). As already noted, one developed a biopsy-positive prostate nodule whereas none of the 15 had a nodule when PSA levels were initially measured. At the end of the study the disease in all of the patients was chemically staged using a PSA reference range of 0.0 to 2.0 ng/mL (Table II). This range proved to have a positive predictive value UROLOGY@ /J~~1995/

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TABLE II.

Staging Traditional (DRE negative) PSA (0.0-2.0 ng/mL) Key: DRE = digital

rectal

examination;

Traditional

Initial No. NED f “/I 29 (83) 22 (63) NED = no evidence

versus chemical

staging

in 35 cases

Final NED No. (%) 25 (71) 15 (43) of disease;

(PPV) of lOO%, a negative predictive of 93%, and a sensitivity of 95%.

False Negative 11 1

NPV = negative

value (NPV)

COMMENT In this study, all patients with a postradiation PSA level of 2.0 ng/mL or less had low PSA velocities, whereas all patients with PSA levels more than 2.0 ng/mL had high PSA velocities. Therefore, the upper limit of the reference range 0.0 to 2.0 ng/mL can be determined by PSA velocity, This range differs from standard PSA reference ranges for normal men over age 40 years.14J5 In 20 men, PSA levels more than 2.0 ng/mL, either initially or when measured later, invariably continued to rise at a rate more than 1 ng/mL per year. Therefore, a significant PSA velocity after radiation therapy could be quantified at more than 1 ng/mL per year. This is similar to the PSA velocity of more than 0.75 ng/mL per year detected by Carter et al. l6 in 18 men over a period of 5 years preceding the development of clinical prostate cancer. And Zagars13 found that men with an initial PSA level more than 2 ng/mL at 3 months after radiation therapy had a significantly worse outcome than those with a lower PSA level. The concept of using chemical failure as an endpoint in measuring treatment outcomes1,4J,g-11J3 is supported by these postradiation studies. The present study suggests that chemical failure after radiation treatment is indicated by a PSA level of more than 2 ng/mL rising at a rate of more than 1 ng/mL per year. In 15 men, PSA levels between 0.0 and 2.0 ng/mL remained stable with one false-negative result. Low and stable PSA levels from 0.0 to 2.0 ng/mL probably indicate cancer control, if not cure. These levels are similar to the range of 1.8 ng/mL or less in 97.5% of men under age 40 years reported by Ahman and Shifmanl’ and a range of 0.0 to 2.5 ng/mL in 95% of men between ages 40 and 49 years reported by Oesterling et at.15 Other investigators 18-20 have suggested using a lower postradiation PSA reference range of 0.0 to 1.0 ng/mL. However, if such a low reference range had been used in the present study, 6 patients

U ROLOCY@ /JUNE 1995 i VOLUME 45, NUMBER 6

predictive

True Negative 14 14 value;

PPV = positive

NPV (%I 56 93

True Positive 10 20

predictive

value; PSA = prostate-specijic

PPV VW 100 100

Sensitivity I%) 48 95 antigen.

would have been falsely considered to have cancer activity. These 6 had stable PSA levels between 1.0 and 2.0 ng/mL and were part of the group totaling 11 patients who had PSA levels of 0.0 to 2.0 ng/mL at a mean post-therapy interval of 84 months (range, 44 to 133; median, 96). Similarly, 3 of 5 patients followed by Zietman et al.18 would have had falsely positive PSA values 8 to 18 years after therapy Therefore, men with PSA levels between 1 and 2 ng/mL may also be cured or at least have obtained effective long-term cancer control. A lower PSA range of 0.0 to 1.0 ng/mL may be a worthy goal, but it would not be a useful standard PSA reference range if it yields too many falsepositive cases. In contrast, use of a PSA reference range of 0.0 to 2.0 ng/mL in the present study avoided the complexities of dealing with falsepositive cases, whereas true-positive cases were readily identified at any time. Even when the PSA level is truly positive, a slow velocity rise in an elderly patient does not necessarily require intervention.12,1g For example, Hanks et al.‘i examined 17 patients with no evidence of disease at 9 to 13 years after radiation therapy. They found PSA levels less than 2.0 ng/mL in 11 (65%) but 2.0 to 3.5 ng/mL in 4 (24%) and more than 4.0 ng/mL in 2 (12%). Since there is wide variability in PSA doubling times after radiation therapy, 22,23 there will inevitably be some patients with the most indolent tumors remaining for analysis after 10 years. There is little lost from the usefulness of a reference range when within the first 10 years it encompasses patients with indolent cancer and stable PSA levels. However, when high PSA velocity determines the upper margin of the reference range, patients with aggressive cancers are promptly revealed. There is a time in this and other studies when the fate of most patients can be determined from true-positive PSA values and when false-negative rates can be established. For example, at 39 months after radiation therapy, 80% (16 of 20) of men who eventually developed chemical failure already had PSA levels more than 2.0 ng/mL rising at more than 1.0 ng/mL per year. This and 1019

other studies13~20~22 suggest that the crucial time for identifying the most aggressive cancers occurs within 4 or 5 years after completing radiation therapy. In contrast to early chemical evidence of failure, 3 men in the present study clearly had falsenegative low and stable PSA levels at 39 months. Because there were 14 men at 39 months whose PSA levels were low and stable, the false-negative rate at this particular time would be 3 of 14, or 21%. (This rate might be different if the 35 patients measured in this study were not the only ones available from a larger cohort when PSA testing first became available.) None of the other 11 men developed any sign of recurrent cancer after 39 months, although 1 had a suspiciously variable PSA at 118 months (Fig. 2). Others studying postradiation patients have noted false-negative PSA levels.1,g When an accurate false-negative PSA rate can be determined from a large group of postradiation patients at, for example, 4 or 5 years, the follow-up period of postradiation research studies can be shortened. Postradiation nadir PSA levels may give the most accurate prognosis for groups or individual patients,24 but what happens after the nadir is more important; the combination of a standard PSA reference level with PSA velocity and accurate false-negative rates would clearly be a useful tool for researchers and clinicians With a defined postradiation PSA reference range for prostate cancer control, chemical monitoring can be compared with traditional methods.1,4,5~10~13~18 In the present study, when rising PSA levels of more than 2.0 ng/mL were used instead of traditional clinical signs of failure, the initial progression-free survival rate fell from 83% to 63% (Table II). At the closing month (mean, 51 * 32; range, 10 to 1331, this rate fell from 71% to 43%. Chemical staging had a sensitivity of 95% and an NPV of 93% compared with traditional DRE staging, which had a sensitivity of 48% and an NPV of 56%. It should be noted that the PPV (that is, the reliability of a positive test) of the PSA reference range 0.0 to 2.0 ng/mL was 100% and was not dependent on any postradiation time interval. In contrast, the NPV (that is, the reliability of a negative test) was strongly dependent on the postradiation time interval; for example, the NPV was 79% at 39 months and 93% when the study was ended at 72 months after the last man was treated. For the individual patient, it would seem prudent to follow both PSA levels and DRE at minimum intervals of 3 to 6 months for up to 4 years. Bone scans would be warranted in selected patients, as Stamey et ak3 noted deceptively low PSA 1020

levels in some postradiation patients with metastases, and 1 patient in the present study had a positive bone scan with a false-negative PSA value at 43 months. Nonetheless, early chemical evidence of cancer activity would allow adjunctive therapy of most aggressive recurrent cancers. The utility of a standard cancer reference range can be measured by its ability to identify aggressive cancers as soon as possible while ignoring indolent cancers or cures. PSA velocity is an objective factor that can define the upper limit of a standard PSA reference range after radiation therapy of patients with cancer of the prostate. Robert W. Geist, M.D. 280 North Smith Avenue Suite 658 St. Paul, MN 55102 ACKNOWLEDGMENT. To John Karrow, M.D., of the Department of Radiotherapy, St. Josephs Hospital, St. Paul, Minn, and to Drs. Stanley J. Antolak, Michael Pergament, Eileen Toolin, Bradley Qualey, and Leslie Rainwater for their cooperation and advice.

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